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Osteoclasts: much more than bone remodelling cells
( PDF ) Rev Osteoporos Metab Miner. 2014; 6 (4): 109-21
Arboleya L1, Castañeda S2
1 Hospital Universitario Central de Asturias – Oviedo
2 Hospital Universitario de la Princesa – IIS-Princesa – Madrid
The osteoclast has been considered classically as a cell with the exclusive function of bone remodelling, with a gregarious behaviour.
However, advances which have been made in recent years have changed this concept drastically, and we now know that this multinuclear cell is subject to complex biological regulation, necessary for it to exert a multifunctional role of unknown dimensions.
In addition to its participation as the only cell capable of reabsorbing the calcified bone matrix, the osteoclast is one of the cellular elements effective in the immune system, a function still little-known but expected, given its belonging to the monocyte-macrophage lineage. Its role in other processes, both local, such as as a collaborative element in osteoformation and hematopoietic stem cell niche maintenance, and systemic, is also beginning to be understood.
In this review the most significant findings contributing to our understanding of the biology of the osteoclast are analysed, with an eminently practical content and an approach aimed at understanding the possible molecular targets which will allow a better therapeutic treatment of such important diseases as osteoporosis, arthritis or cancer.
Keywords: osteoclasts, osteoporosis, arthritis, RANKL.
Osteoclasts (OCs), as the only cells capable of extracting the calcified bone matrix, are the protagonists in the delicate task of dissolving the crystals of calcium phosphate and digesting the collagen, by means of highly specialised structures [1]. Their pathogenic role in the induction of excessive bone resorption observed in pathological processes such as osteoporosis [2], arthritis [3], or cancer [4], is fundamental. The notable advances which have occurred since the start of this new century have allowed us to understand the intimate mechanisms which regulate the formation, activity and survival of OC, opening new possibilities for the design of drugs with more specific actions than those that already exist.
In recent years, the scientific effort dedicated to understanding the complex resorptive mechanisms has grown exponentially, with great advances being made through three main lines of research: 1) the study of a series of genetic diseases, relating the phenotypes observed to the dysfunction detected; 2) experimental studies based on the creation of animal models in which a determined gene is annulled or overexpressed; and 3) by obtaining precursors and mature cells in culture and analysing their responses to various stimuli. Taking into account the fundamental importance of OCs in the pathogeny of such significant diseases as arthritis, osteoporosis and cancer, along with the enormous quantity of information which has emerged in the last five years, we consider it necessary to carry out a review to update our knowledge in this important area of research.
General characteristics of osteoclasts
OCs are located on the internal surfaces of the Haversian canals of the cortical bone, in the trabeculae large than 200 microns and in the external walls of the bone, beneath the periosteum. Although potential precursors may be found in the peripheral blood, spleen and bone marrow, the mature cells are very rarely found away from the bone surfaces, except in pathological situations, such as in giant cell tumours. In the absence of the specific situation of high levels of remodelling, such as occurs at the metaphysis of the long bones during growth or in diseases such as primary hyperparathyroidism, OCs are scarce in the skeleton since they only comprise 1-2% of bone cells. They have a half-life of two weeks, and in normal conditions, after this period, undergo apoptosis [5].
In spite of their rarity in samples of non-decalcified tissue, their morphology is characteristic when activated, which enables them to be easily recognised as strongly polarised multinucleated structures, with a basal region for the interchange of external signals and a zone joined to the calcified matrix by a structure called the brush border. The OCs move, by means of podosomes, over the calcified surfaces, on which a single cell can form consecutively a number of Howship's lacunae. They have a number of immunohistochemical characteristics which facilitate their identification, among which are the expression of tartrate-resistant acid phosphatase (TRAP). Although TRAP mRNA has been identified in other tissues, such as the kidney, intestine and lung, as well as in activated macrophages, this enzyme continues to be an essential osteoclast marker whose expression appears very early, immediately before the mononuclear OC initiates the fusion mechanisms, increasing progressively through the different post-fusion stages until maturity is reached.
The OCs belong to the monocyte-dendritic-macrophage lineage, although, differently from other members of its progeny, it has the capacity to bond to bone by means of the αvβ3 integrins, which are expressed in the surface of the podosomes and which have the property of interacting with the proteins of the matrix, such as osteopontin and vitronectin. Following the primary activation signal, the multinuclear OC is polarised and is stuck to the bone surface by means of specialised structure known as the brush border, at the ends of which are found the integrins which become bonded to the matrix producing a hermetic seal with the lacuna, an essential step for the interchange of ions and proteases necessary for proper bone resorption.
The basolateral zone of the membrane does not undergo significant morphological changes, but will play a role, which is poorly-understood, in cell communication and in the transport of ions. In the osteoblast cytoplasm there is a high level of carbonic anhydrase II activity which causes a dissociation of the cytosolic carbonic acid into protons (H+) and bicarbonate (HCO3−), the latter interchanged with chloride (Cl−) by means of a specific channel, which allows the conservation of the intra-cellular isoelectric state. The proton is directed to the brush border, where a proton pump dependent on a specific ATPase (H+-ATPase) transports it to the lacuna. In the vicinity of this pump is situated an ion channel (chloride 7 channel, ClC7) which is a simple ion interchanger which uses voltage gradient to obtain the energy necessary to transport them through the membrane. Specifically, this channel interchanges 2 Cl− for 1H+, and its function is highly important in the processes of lysosome acidification in general [6] and in bone resorption in particular.
The loss of function of the ClC7 is one of the most common causes of osteopetrosis [7] and is, together with the proton pump, an interesting therapeutic target [8], but limited, at the moment, due to the consequences of its extra-skeletal actions, above all, the risk of production of lysosomal diseases [9]. In the lacunae, through the union of these two ions, hydrochloric acid is formed, which acidifies the environment causing the hydroxyapatite to dissolve, liberating calcium and phosphate, while at the same time maintaining the cytoplasmic ionic charge in equilibrium. Lastly, through the lysosomes, a cysteine protease, cathepsin K, and a series of metalloproteases are secreted which, finally, cause the dissolution of the organic matrix. The resulting degradation products enter the OC by endocytosis and are transported to the basolateral region in vesicles rich in TRAP and released to the exterior by exocytosis.
Formation and activation of osteoclasts
The osteoblasts (OB) of mesenchymal origin reside, essentially, in the bone tissue and the adjacent bone marrow. However, the OCs and their precursors are a highly dynamic population, and the mechanisms which control their migration and arrival at the bone surfaces have recently emerged as essential elements of the homeostasis of the skeleton. OCs derive from hematopoietic stem cells, which will lead, through myeloid progenitors, to circulating monocytes and tissue macrophages [10]. The target organ will define the final characteristics of these cell populations, emitting different signals which will determine their different morphological and functional qualities: Küpffer cells in the liver, alveolar macrophages in the lungs, microglia in the central nervous system, histiocytes in the connective tissue, dendritic cells and macrophages in the lymphoid organs, and OCs in the bone. In spite of the fact that many of the properties of these differentiated myeloid cells, essentially their structure and function in the tissues, are known, there is still very little known of the intimate mechanisms which govern their differentiation and dynamics.
Migration of the precursors
Mononuclear lineage cells with the capability of differentiating into osteoclasts have been found in the bone marrow and in the bloodstream [11,12]. Although it is not known if there is a mononuclear precursor population specific to OCs, it is known that certain sub-classes of circulating monocytes and dendritic cells, as well as progenitor cells of monocyte-macrophage lineage resident in the bone marrow, have the capability of being transformed into OCs if they are subject to certain specific signals [13]. Using innovative fluorescence techniques which allow the visualisation of the behaviour of cells in vivo, Kotani et al. have recently shown that the mature OCs situated in the resorption surfaces come from the circulating monocytes which migrate to these regions of the bone where they undergo fusion, polarisation and development of the elements of the cytoskeleton which characterise active OCs [14].
The signals which attract the circulating precursor population towards the bone surfaces are starting to become understood, constituting an interesting group of molecules of potential therapeutic interest. These cells, which should express RANK in their membranes, become attracted to the bone marrow or the quiescent surfaces where, after receiving the RANKL signal, they are transformed into mature, polarised OCs with the characteristic cytoskeleton. This main signal comes from the mesenchymal cells of the bone marrow, from lining cells or from the osteocytes situated in the depths of the calcified matrix.
The RANKL signal is essential for the final activation of the OCs, although it is probably only executed in the target organ, there being signals which we could consider to be "anterior" which provoke the migration of the precursors from the circulation system. To date, various recruitment signals have been identified, notable among which is chemokine CXCL12, strongly expressed in stromal cells located in the perivascular regions of the bone marrow. The osteoclast precursors express the receptor of chemokine CXCR4, whose union with CXCL12 promotes the recruitment and survival of the OCs [15]. The CXCL12/CXCR4 axis has become a target of great interest in oncology [16,17] due to its key role in the migratory behaviour of tumour cells, although, taking into account the above, it is highly probable that it also participates in functions such as accelerated bone remodelling which occurs in postmenopausal osteoporosis, or in the different forms of bone destruction which characterise rheumatoid arthritis.
Another chemokine axis of interest is that featuring CXCL1 (fractalkine), expressed in osteoblasts, and its receptor, CX3CR1, expressed in OCs whose action could also be important in the recruitment of precursors [18]. Nevertheless, the design of small molecules with activity inhibitory to chemokines [19] is encountering a number of difficulties due to the toxicity caused by their poor specificity.
Another group of molecules with recruiting action are the bioactive sphingolipids. Known for their structural role in cell membranes, they have acquired additional importance due to their being precursors of molecules with a strong chemotactic capacity, such as sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) [20,21]. The latter, with significant roles in the function and dynamics of other myeloid populations [22], does not appear to intervene in the migration of the OCs, with, to date, no receptors associated with these cells having been identified.
S1P is the product of the phosphorylation of sphingosine by two kinases, sphingosine-kinase 1 and 2, a reaction which is activated in response to a number of mediators which include various cytokines and hormones. After its synthesis it may be activated in the intracellular environment but also be released into the bloodstream, where it interacts with at least five G protein-coupled receptors, of whichS1PR1 and S1PR2 have been identified in osteoclast precursors [23,24]. After the bonding of S1P to its receptor, this is rapidly internalised in a way very similar to that which happens with the bonding of the ligand to CXCR4, and, at the present time, this is considered to be a highly significant factor in the dynamics of hematopoietic progenitor cells and in the traffic of immune cells between the lymphoid organs and the peripheral tissues. Its role in bone diseases is beginning to be understood, it having been observed that low concentrations of S1P are chemotactic for the osteoclast precursors, while high concentrations have the opposite effect. S1PR2-nul mice develop osteopetrosis, while in ovariectomised rats, the S1PR2 antagonist, JTE013, slows osteoporosis, reducing the number of OCs [24]. Contrarily, the ablation of osteoclast S1PR1 causes osteoporosis [25].
These facts suggest the existence of a fine control of osteoclast migration dependent on the gradient of S1P [26], which may be summarised as follows: in the bloodstream there is a high concentration of S1P, while in the bone tissue it is lower. The skeletal OCs, after the activation of the S1PR1, migrate towards the circulation system, while the activation of S1PR2 exerts an opposite effect, inducing migration in the opposite direction, with OCs accumulating in the bone. We are, therefore, looking at a molecular system of therapeutic interest [27-29], since the stimulus of S1PR1 or the blocking of S1PR2 causes an antiresorptive effect notable in murine models in, respectively, provoking the departure or slowing the arrival of OCs to the resorption sites.
Regulation of osteoclast differentiation
Osteoclast differentiation is a strongly regulated process whose study has been limited due to the necessity of using mixed cultures of osteoblasts and OCs to obtain mature cells [30]. Since the discovery of RANKL, the advance in the knowledge of these mechanisms has been enormous by making possible the culture of isolated osteoclast precursors in the presence of RANKL without the need for the interaction of other cells [31]. It is widely known that the mature OCs are the only cells in an organism capable of reabsorbing bone [32]. Nevertheless, to achieve the development of their complete resorptive mechanism the osteoclasts have to undergo a profound transformation after their arrival in the proximity of the mineralised surfaces, which starts with the initial intervention of M-CSF and the expression in its membrane of RANK (Figure 1). At present, the mechanism by which a sub-group of multipotential mononuclear precursors begin to express RANK in their membranes, and as a consequence, follow the path to differentiation as osteoclasts after being exposed to RANKL [33], is not known.
a) M-CSF signal
After the initial expression of PU-1, a transcription factor required for the generation of the progenitors of the lymphoid and granulocyte-macrophage series, which acts in the very early phases of myeloid differentiation, the expression of c-Fms occurs, the receptor of M-CSF which will characterise the population of the primitive osteoclast precursors [13,34]. After its union with the ligand, the c-Fms, as with other members of the super-family of tyrosine-kinase receptors to which it belongs, is phosphorylated and activated to ERK (extracellular signal-regulated kinase) through GRB-2 (growth factor receptor bound protein 2) and to AKT through Pl3K (phosphoinositide 3-kinase), provoking cell proliferation signals. In addition, through the activation of MITF (microphthalmia-associated transcription factor) the expression of Bcl-2 (anti-apoptotic B-cell leukaemia/lymphoma-associated gene 2) an essential factor for survival, is induced [35-38]. Lastly, the expression of RANK occurs in the membrane of the precursors, which will enable the action of RANKL on these cells and their final differentiation into mature OCs.
b) RANKL signal
RANK lacks intrinsic enzyme activity in its intercellular domain and needs to transduce the signal from the ligand through the recruitment of adaptor molecules, among them TRAF-6, GAB-2 (Grb-2-associated binder-2) and phospholipase C. The last two of these are not indispensable in the initial phase but are necessary in a subsequent amplification phase [39]. However, TRAF-6 is essential to activate the distal signal, in which NFkB, AP-1 and various MAPKs (mitogen-activated kinases), above all JNK (Jun N-terminal kinase), p38 and ERK, are involved.
The activation of NF-κB is one of the earliest and most crucial molecular events which occur after the union of the ligand to RANK. NF-κB belongs to a family of dimeric transcription factors which, in the non-activated cell, stays captive in the cytoplasm due to being bonded with inhibitory proteins called IkB (inhibitors of κB kinase). The RANKL/RANK/TRAF6 signal provokes the proteolysis of these inhibitors, which allows the translation to the nucleus of free NFkB, where it bonds with DNA response elements, inducing the transcription of the target genes [40]. This intracellular signalling pathway participates in the regulation of various genes involved in immune and inflammatory responses, which produce cytokines such as IL-1, IL-2, IL-6, IL-7 and TNF, chemokines, interferons and anti-apoptotic proteins, such as BIRC2, BIRC3 and BCL2L1. In humans, the deregulation of NF-κB is associated with various diseases such as diabetes mellitus, Alzheimer's, autoimmune diseases, osteoporosis and arthrosis, and is a potential therapeutic target, partly limited by its non-specificity [41].
RANK also induces the activation of NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1), currently considered to be the master regulator for osteoclast activation [42]. NFATc1 belongs to the family of NFAT transcription factors, identified initially in nuclear extracts of activated T-lymphocytes [43]. In subsequent studies it was shown that its role in osteoclast activation was significant when it was observed that the monocyte-macrophage precursor cells in bone marrow stimulated by RANKL had a selective and marked overexpression of NFATc1 [44]. The activation of this factor is dependent on NFkB and c-Fms, probably in this order [45].
c) Co-stimulation and amplification of the RANKL signal
Coordinated with the RANKL signal other transduction pathways for inductor signals for NFATc1 have been observed in the OC (Figure 2), whose role could be decisive in pathological states [46]. At least two Ig-like receptors are known: OSCAR [47] (osteoclast-associated receptor) and TREM-2 [48] (triggering receptor expressed in myeloid cells). Both are associated with adaptor proteins which contain ITAM (immunoreceptor tyrosine-based activation motifs) motifs such as DAP-12 (DNAX-activation protein 12) or FcRγ (Fc receptor common γsubunit). Although the ligand for these receptors is not known with any certainty (recently OSCAR has been associated with specific motifs expressed in fibrillar collagen) [49], when activated, the phosphorylation of the ITAMs by tyrosine-kinase occurs and, in collaboration with other molecules such as BLNK (B cell linker protein) and SLP76 (Src homology 2 domain-containing leukocyte protein of 76 kD), the activation of PLCγ2 is then provoked, contributing to the amplification of the RANK signal. It is not known whether these pathways are significant in physiological states, although in pathological situations such as osteoporosis, arthritis or cancer, it is highly probably that their over-activation contributes to the state of marked osteoclast stimulation which they exhibit [47-52].
NFATc1 is a regulator central to osteoclast activation, both in the sense of being a stimulator of the RANK signal and in the opposite sense, as a target for different molecules which inhibit its expression. In the positive sense, the expression of NFATc1 induced by RANK/NFkB/c-Fos is dependent on the signalling pathway p38. Other signals, coming from Ig-like receptors associated with adaptor factors such as FcRγ y DAP12, act in a coordinated way with the above signals through the transitory increase in intracellular levels of calcium, due to mechanisms not yet clarified which could also involve PLCγ2, which then activates calcineurin. This enzyme dephosphorylates the cytosolic NFATc1, which allows its translocation to the nucleus, where, in concert with PU.1 and MITF, it goes on to activate the promoter regions of various genes which code for molecules essential for osteoclast function such as cathepsin K, OSCAR, DC-STAMP, TRAP and V-ATPase-d2. In addition, there is an increase in its own synthesis through a process of auto-amplification described in 2005 by Asagiri et al. [45]. However, these secondary activation pathways of NFATc1 are dependent on the main pathway and, in the absence of RANKL, and no stimulus occurs in isolation from these receptors, leading to an absence of osteoclast activation [53].
To avoid unchecked osteoclast formation which would result from the NFATc1 pathway, there is a series of negative regulators which act on this factor, generally indirectly through the proximal signal [54]. Within the group of cytokines, IL-4 and IL-13, products of the Th2 cells, perform pleiotropic functions, among which is a powerful anti-osteoclast action which is executed in way which is dependent on STAT-6 (signal transducer and activator of transcription 6) with the final result being the expression of NFATc1. Other cytokines such as IL-10, IL-27 or IFN-γ inhibit the formation of OCs from their precursors or their activation, through mechanisms dependent on the RANK/NFkB/NFATc1 signal [55].
The activation of various TLRs (toll like receptors) reduces the rate of formation of mature OCs induced by RANKL through IFN-β-dependent mechanisms, although independent mechanisms have also been observed. On the other hand, the activation of TLRs is one of the most powerful inductors of inflammatory cytokines, such as TNF and IL-1, which act synergistically with RANKL in the production of inflammatory osteolysis in diseases such as rheumatoid arthritis or periodontal disease [56].
In brief, we may intuit that the TLRs, as key elements in the innate immune system, have an antagonistic role strongly dependent on context. On the one hand, by initiating the inflammatory response, the transformation of precursors into OCs would reduce, which would increase the pool of cells available for transformation into macrophages. However, in a more advanced stage, if their activation persisted in a sustained way, they would act as inductors for osteoclastogenesis, indirectly by means of inflammatory cytokines. The confirmation of this attractive hypothesis would constitute one more element to support the idea of the OCs' significant participation in the immune response.
There are other factors which inhibit the formation or activation of the OCs in addition to those already cited: cytokines such as TRAIL [57] (TNF-related apoptosis inducing ligand), IL-12 and IL-18 [58], different intracellular signalling molecules such as SHIP1 [59] (Src homology 2-containing inositol-5-phosphatase 1), NF-κB p100 [60] and some components of the Notch pathway [61], various transcriptional repressors such as MafB (v-maf musculoaponeurotic fibrosarcoma oncogene family protein B) [62], C/EBPβ (CCAATenhancer-binding protein β) [63], IRF-8 (Interferon regulatory factor) [64], and BcL6 (B cell lymphoma) [65]. All these molecules are potential targets of therapeutic interest, but their detailed analysis is beyond the scope of this review.
d) Osteoclast activation pathways independent of RANKL
The RANKL signal is the most important osteoclast activation pathway and its annulment in murine models results in the complete disappearance of the OCs, which means that the role of pathways independent of activation appear, in theory, to be unimportant. However, in 2005 Kim et al. demonstrated that the presence of cofactors such as TGF-β, the hematopoietic precursors in mice null for RANKL, RANK and TRAF-6 would succeed in being differentiated into OCs [66]. It is evident that the interest in this topic is enormous, since there could be, at least in pathological circumstances, non-canonical osteoclast activation pathways which could be modulated to achieve different therapeutic responses to the complete annulment of OCs.
Within the TNF superfamily, given the structural homology between its members, various ligands and receptors have been investigated. One of the most interesting is LIGHT (also known as TNFSF14 and CD258). This type II transmembrane protein is expressed primarily in activated T-cells, NK cells, dendritic cells and macrophages, performing key biological functions in the innate and adaptive immune responses through the homeostasis, differentiation and activation of the T-lymphocytes [67]. It joins three receptors which share a structural similarity in their cytoplasmic stem: TNFRSF14/HVEM (herpes virus entry mediator), LT-βR (lymphotoxin β receptor) and DcR3 (decoy receptor 3) [68]. Although the role of LIGHT in bone resorption is not known, it has been observed that it causes a powerful osteoclastogenetic action independent of RANK and OPG, through AKT, NFkB and JNK in human and murine monocytes, using TRAF-2 and TRAF-5. Its function in bone diseases has not been clarified, but it is, without a doubt, an interesting target of potential therapeutic interest [69,70].
Two other members of the TNF superfamily have shown an osteoclastogenetic capability independent of RANKL. APRIL (a proliferation inducing ligand, TNFSF13) and BAFF (cell activating factor belonging to the TNF, also known as BLyS and TNFSF 13b), are capable, in in vitro culture, of inducing cells with the osteoclast phenotype from mononuclear precursors, although of a smaller size and with a lower number of nuclei and resorptive capacity than those induced by RANKL or LIGHT [71].
e) Origin of RANKL in osteoclast activation
Although the origin of RANKL which is involved in bone remodelling is classically thought to be the OBs, there have been a number of experimental findings which have cast doubt on this idea. In a pioneering study, Corral et al. [72] showed that the ablation of osteoblast progenitors by the administration of ganciclovir in mice bearing a thymidine-kinase transgene under the control of the osteocalcin promoter, did not cause any effects on the osteoclastic surfaces or on the markers for resorption, even after several weeks of follow up, in those in which the population of osteoblasts had disappeared from the bone surfaces. More recently, and using a similar transgenic murine model, Galli et al. observed that the absence of osteoblasts did not affect the levels at the baseline, or after being stimulated by PTH, of RANKL mRNA [73]. These studies indicate that the classic paradigm, which is that the RANKL which governs osteoclast activation comes from OBs or their precursors, should be revised [74].
OCs are formed in different locations in the skeleton with different purposes and with a variety of support cells charged with synthesising the RANKL necessary for their activation. For example, the femurs of mice which lack osteocytic RANKL develop a normal morphology, which indicates that the cortical modelling of the long bones is controlled by cells other than the osteocytes; whereas during chondral ossification, the main source of RANKL, which enables the reabsorptive action of the osteoclasts on the calcified cartilage, are the hypertrophic chondrocytes [75]. The OC is also the effector cell for the erosion which characterises rheumatoid arthritis [76,77], and its activation is supported by the collaboration of the synovial cells of fibroblast lineage of the lymphocyte subclass Th17 [78]. These facts suggest that the role of RANKL derived from the osteocytes could be limited to bone remodelling.
The osteocyte is a cell which provides a large amount of RANKL during physiological remodelling [79]. This fact is even more plausible from the biological point of view due to the known role of these cells in the detection of both mechanical and hormonal signals, which enables them to act at true regulators of bone remodelling, at least in physiological conditions. Using Cre-LoxP technology, which allows the modification of DNA in specific types of cells, Xiong et al. [74] caused the deletion of the osteocyte RANKL gene in mice and observed a reduction in OCs, with an increase in bone mass and of the markers for resorption, without alterations in the development of the skeleton or in dental eruption. In the laboratory of Takayanagi [79] the same results were obtained using similar technology. In summary, these studies demonstrate that osteocytes are the main producer cells for RANKL in physiological bone remodelling.
The RANKL which comes from the osteocyte is, therefore, the cytokine which controls physiological bone remodelling in response to mechanical and hormonal signals. The mechanism by which RANKL accesses OCs has not yet been sufficiently clarified. There is experimental evidence that the presence of soluble RANKL in the medium is sufficient to produce osteoclast expansion [80] and that the osteocytic projections express RANKL from the membrane and reach the bone surface where they make contact with the OCs and their precursors [64,81]. Finally, there is evidence that, both through the production of soluble RANKL and through that expressed in the membrane by the dendrites, the osteocytes control osteoclast activation. It has a dual role, since it also possesses the capability of producing sclerostin through the activation of its gene, SOST, and so contribute to the regulation of osteoformation [82].
Osteoclastic fusion
The osteoclast precursors are mononuclear cells which express TRAP, with no resorptive capability in in vitro cultures. The first step by which they acquire their functionality is through cell fusion, which then enables the formation of mature OCs. Understanding the intimate mechanisms which control this critical event in the physiopathology of remodelling is fundamental to the development of the new therapies.
In physiological conditions, the pre-OC TRAP cells + and the mature OCs are only found on the bone surfaces, which indicates that the fusion occurs in these locations. Using techniques of DNA subtraction in precursor cells stimulated by isolated M-CSF or M-CSF and RANKL, it was observed that DC-STAMP (dendritic cell-specific transmembrane protein) is an essential molecule for the fusion of mononuclear cells as a first step for the formation of active mature OCs. This transmembrane protein, discovered in 2000 [83], is also expressed in dendritic cells and macrophages [84]. Its annulment in murine models provoked osteoporosis associated with a complete absence of fused mononuclear OCs as well as foreign-body giant cells. In these mice there persisted a moderate degree of resorptive activity in the mature cells, which indicates that their fundamental role is performed at fusion [85]. The regulation of DC-STAMP is complex and depends not only on the RANKL/RANK pathway but also on other independent factors, such as IL-32 [86], Tal1 (T-cell acute lymphocytic leukemia 1) [87], LDLR (low-density lipoprotein receptor) [88], CCN2/CTGF (CCN family 2/connective tissue growth factor) [89] and vitamin E [90], among others, whose role is even less well known but which could be future targets of therapeutic interest.
OC fusion is promoted by other molecules such as the inflammatory cytokines. Among these, in addition to the actions already mentioned of RANKL, both TNF-α and LPS (lipopolysaccharide) are capable of inducing OC fusion under certain circumstances. For example, the action of TNF-α is specifically blocked by Ac anti-TNF-α, while the effect of LPS is partly blocked by these drugs, and completely blocked by polymyxin B [91]. The activation of these pathways is accompanied by intracellular signals dependent on kinases, and when inhibitors are used specific to these pathways OC fusion is reduced, while levels of DC-STAMP are not altered. These findings indicate that there are alternative pathways which regulate OC fusion independently of DC-STAMP, although it is not known if they exert physiological functions or only interfere with pathological processes [92].
Additional roles for osteoclasts
In addition to their function as the only cells capable of reabsorbing calcified bone matrix, OCs participate in other processes which we summarise below.
1. Stimulation of bone formation
Bone remodelling is a coupled process in which the osteoclast activity is followed by the action of the osteoblasts. The pharmacological inhibition of the former provokes a reduction in the latter, while the osteoforming stimulus is followed by a secondary increase in resorption. In principle, the model would appear to be simple, attributing to factors released from the matrix reabsorbed by the OCs a role in the recruitment of osteoblast [93,94]. However, in a study published in 2001, the Molecular Biology Group of the University of Hamburg demonstrated that, in some murine models of osteopetrosis and in a patient with the malignant infantile form, in spite of a functional alteration in the resorptive mechanism in the presence of a normal number of OCs, such as is produced with the annulment of the chloride channels ClC-7 C, there was normal bone formation [7]. This fact suggests that there are factors independent of the matrix reabsorbed by the OCs whose role in the coupling is probably more significant.
Among the mechanisms in which OCs intervene directly stimulating osteoformation, the following have been proposed [95]: on the one hand, ephrin B2, expressed in the osteoclast membrane, is capable of provoking an activation signal by bonding with its osteoblast receptor EphB4; also, sphingosine-1-phosphate is capable of causing the recruitment of osteoblast precursors to the remodelling sites [96], although treatment with analogues of this molecule has not shown significant results in the mending of fractures [97]. OC expresses, in addition, regulatory factors negative to osteoblasts, such as Atp6v0d2 (a subunit of the V-ATPase proton pump) [98]. Even though the physiological role of these molecular signals is not known, the findings which have been commented on suggest that the intervention of the OCs in remodelling is not limited to bone resorption, but that they also play a significant role in the coupling through molecular signals which participate in the recruitment, activation and inhibition of the osteoblasts.
2. Immune cells
Both OCs and OBs have the capability of responding to a wide variety of cytokines produced by the cells of the innate and adaptive immune systems [78,99-101]. The OCs contain all the mechanisms necessary for endocytosis and the processing of exogenous proteins coming from the material generated during resorption and in pathological situations such as osteomyelitis. In 2009, Kiesel et al. [102] demonstrated that the OCs could recruit T CD8+ FoxP3+ cells and present their antigens. These cells would play a regulatory role, whose function in non-inflammatory situations is unknown. A very attractive but non-proven hypothesis relates this capacity of the OCs as presenters of antigens to the existence of a large reservoir of CD8+ central memory T-lymphocytes in the bone marrow, the former participating in the latter's recruitment and maintenance [103].
The extraction of necrotic bone during a bacterial infection is another of the mechanisms in which OCs play a part in the immune response. In fact, in an elegant study in which murine models which emulated the biology of osteomyelitis and of periodontal implants were used, Li et al. [104] demonstrated that the functional inhibition of the OCs by bisphosphonates and by osteoprotogerin was associated with an increase in the quantity of necrotic cortical bone around the implant which acted as nests for the bacterial colonisation, while at the same time reducing the size of the drainage orifice through which the opsonised bacteria were expelled to the exterior of the lesion. These data are highly significant since they suggest that the pharmacological inhibition of osteoclasts could be contraindicated in bone infections, as well as in the pathogenesis of osteonecrosis of the jaw, where bacterial colonisation is very important, and where OCs would play a key role, at least in its initial phases.
3. Articular cartilage
In those process in which the destruction of hyaline articular cartilage occurs, giant multinucleated cells have been observed which express the osteoclast phenotype (TRAP+, cathepsin K+, MMP9+, CD14−, HLA-DR−, CD45+, CD51+ and CD68+). These cells, called "chondroclasts" in some publications, have the capability of reabsorbing the cartilaginous matrix and have been implicated in the pathogeny of diseases such as rheumatoid arthritis or arthrosis [105]. Their specific role has not been established with any certainty, although there is various indirect evidence to suggest that they may play a significant role on articular damage. It is known that 30% of the total RANKL which is produced in arthritic joints is synthesised in the cartilage, essentially through the chondrocytes [106]. The soluble part of this cytokine acting like a paracrine, may participate, through osteoclast activation in locations of chondral-sinovial contact, in the pathology of erosion and of juxtaarticular osteopenia, which characterise rheumatoid lesions. Furthermore, even though it has not been demonstrated with sufficient certainty, chondrocytic RANKL may contribute to the transformation and activation of the mononuclear precursors, resulting in chondroclasts capable of degrading the cartilage. The mechanisms through which this action would occur is not yet known, but there is, undoubtedly, an interesting question to be asked based around about the possible therapeutic role of the inhibitors of RANKL in processes such as arthrosis.
4. Energy metabolism
Osteocalcin, a small peptide produced by osteoblasts, stimulates the secretion of insulin by the beta pancreatic cells, a finding of enormous importance in decisively implicating bone tissue in the hormonal control of energy metabolism [107]. This molecule has a number of the characteristics of a hormone: it is a specifically cellular product, synthesised in a pre-propeptide form and secreted into the circulation after a process of vitamin K-dependent gamma-carboxylation. This fact explains its great affinity for the bone matrix, which causes it to be released during bone resorption and converted into its active form after exposure to the acid pH of the resorption lacuna. In transgenic mice which lack V-ATPase activity, hypoinsulinemia and glucose intolerance associated with reduced levels of osteocalcin are observed [108]. A study which analysed the effects of alendronate in a small sample of patients showed reduced levels of infra-carboxylated osteocalcin which is associated inversely with an increase in body weight and of fat mass [109]. However, a review of the results of the FIT, HORIZON and FREEDOM studies did not show any alteration in these parameters, nor in glucose metabolism [110]. In summary, while animal models suggest a role for bone remodelling in the control of energy metabolism, the studies carried out in humans show discordant results which need to be clarified in the future [111].
The OC has been considered classically to be a cell whose function is exclusively that of bone remodelling, and which exhibits gregarious behaviour. However, in the last decade experimental findings have drastically transformed this over-simplistic view. The OC shares common origins with the cells of the immune system, both in the myeloid and the lymphoid series. Its role in articular inflammatory diseases such as rheumatoid arthritis is probably highly significant, since, to its well-known function as the only cell capable of dissolving the calcified bone matrix, are added new roles due to its capacity to secrete cytokines and as an antigen presenter cell. OCs, as extraordinarily dynamic cells, are therapeutic targets of enormous interest (Table 1) due to their participation in processes such as osteoporosis, arthrosis or cancer.
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I recently picked up an interesting little tube amp via a group buy on Massdrop, the Gemtune APPJ PA1501A stereo tube amplifier. Try saying that three times fast! It's a cute little single-ended stereo tube amp using a pair of 6AD10 Compactron tubes which have two functional sections, one voltage amplifier pentode used for the amp's input stage, and a beam power tetrode used for the amp's output stage that's fairly similar to a single-ended old school (no suffix) 6L6. The manufacturer suggests it's good for 3.5W of output power, single-ended, per channel. And it looks good, too! Not bad for under $200.
The 6AD10 Compactrons used in this amp were originally used as integrated audio sections (detector/driver and output) in a number of televisions and combination units towards the very end of the tube era but not many other places, so while they're not as common of an "odd tube" as something like a 5AQ5, etc. they're readily available, and they don't get talked up much for audio use other than in this amp (and rebranded versions thereof) and some sites about homebrewing with junkbox tubes. As such, NOS replacements can be had for as low as $5 if you want to try different brands of tubes and see how they change the sound.
The amp is physically quite small, under 6″ cubed, and has a very minimalist design. Everything is in mid-matte silver with subtle labeling, also available in black. There's a single volume control on the front sporting a machined metal knob that feels decently weighty, a pair of ceramic 12-pin Compactron sockets, and output transformers hidden inside shrouds with banana plug ports on the rear. The manufacturer names the output transformers as Japanese Z11-EI48 models which I assume is meant to signal quality, although there's still no substitute for more iron in and output transformer no matter how carefully the laminations are stacked and windings are threaded.
There's also the input RCA jacks, IEC power input, fuse, and switch. Very minimalist. The banana plug spacing is perfect to accommodate standard separate, or dual banana plug arrangements. With only one input (and a low power rating), this is really meant to be a single-source desktop amp driven from a DAC or high-end sound card.
Inside, there's a switching power supply and an assortment of Nichicon and Rubycon capacitors. There appears to be a solid-state stage ahead of the tubes based on the TO-220 transistors up near the volume control.
Lifting off the top, there's a shield protecting the output transformers from picking up interference from the switching power supply located below them, and an assortment of passive components supporting the gain stage and power stage of the 6AD10 tubes. There are also a pair of LM431 "Adjustable Precision Zener Shunt Regulator" in an SOT-23 package to provide power regulation.
Time to see how it stacks up. I used a set of Klipsch RB-4 II desktop speakers, and a set of Ohm Acoustics Model D speakers for sound tests. For test equipment, I used the Keithley 2015P multimeter for some quick checks, the Sencore PA81 Stereo Power Amplifier Analyzer, and the Audio Precision System One. All tests – both listening and performance – were administered after the amplifier had a chance to break in by playing a 1 kHz tone into an 8 Ohm dummy load for approximately 8 hours, then sat overnight, and allowed to warm up for 15 minutes before testing to ensure everything has had a chance to unlimber after manufacturing and shipping.
I'd have to say that I enjoy the sound of the amp well enough. Both the Klipsch and Ohm speakers are quite efficient, and I never felt like it was really straining to give me the volume I wanted, without much distortion. Mid-bass through treble was well defined, but the bass was much more reserved than I expected it to be given the published specifications. The amp itself was very quiet even with the volume turned up at no signal, somewhat surprisingly. Running in Class A certainly helps.
The fit and finish was probably a 7/10. Some of the machined edges were a bit rough, and the machined knob manages to actually be *sharp* in one spot. The volume knob doesn't rotate perfectly smoothly through it's travel, it binds slightly in the middle. The transformer covers are a nice touch with the standard-spacing banana plug receptacles on the rear, but it's also obvious they're concealing small output transformers. With an output transformer, the more iron you have the better bass you'll get. Small transformers limit the low-end power available but large, good quality transformers quickly get expensive.
The electrical measurements did put the feeling about the bass into some context. First, the output transformers appear to be designed for an 8 ohm nominal load, as that's where they delivered the greatest output power. 6- and 4-ohm connections delivered lower amounts of power respectively due to the mismatch but only moderately. At 4 Ohms, the apparent power reduction was around 10%. Both the power output sensitivity measurement, and the frequency response, were somewhat out of bounds however.
Gemtune proposed 3.5W into 8 Ohms with 500 mV sensitivity, in other words, with the volume control turned to maximum applying a 500 mV signal to the input jacks will cause the amplifier to deliver 3.5W into an 8 Ohm load. As shown on the "Sensitivity Into 8 Ohms" my example of the amplifier fell somewhat short of this goal, delivering only 2W at that input level. It took about 1.5V at the input terminals for 3.5W output.
Into 4 Ohms, the amp fared even worse making about 1.7W with 500 mV, rising to 3W at 2V. At those power levels, I'd be worried about damaging something if operated that way long-term. The kink in the sensitivity charts occurs about 700 mV and gives about 3W into 8 ohms or 2.7W into 4 Ohms, above that it tapers off as the output tubes are being pushed to their maximum and more input signal can't drive them any harder. I wouldn't recommend driving it harder than 700 mV at full signal, which caps this amp's effective power to just shy of 3W into an 8 Ohm load and a little lower into a 4 Ohm set of speakers. Due to individual differences in the tubes, the power output starts to diverge at the extremes of the chart. More markedly at 8 Ohms than 4, interestingly enough, likely due to the lower overall power output at 4 Ohms.
Frequency response, 10 Hz – 100 kHz, into 8 Ohm load. 0 dB @ 1 kHz.
Frequency response, 20 Hz – 20 kHz, into 8 Ohm load. 0 dB @ 1 kHz.
The frequency response was given as 30 Hz – 40 kHz +/- 1 dB. I'll give them "close enough" on the high end (-1 dB just shy of 40 kHz) since that's well beyond human hearing anyway. The low end was a bit disappointing, though, with the published roll-off being more optimistic than reality proved. The channels diverged by 0.5 dB on the low end, although as the channel separation is less than the flatness specification (0.5 dB < 1 dB) this isn't something where I'll give them a negative mark. However, the -1 dB point was located at about 46/55 Hz; at 30 Hz it's down to -2.3/-2.65 dB and at 20 HZ it's down to -4/-4.55. This definitely explains why I felt the bass was a bit lacking.
That's not to say I think the amp is a bad performer. I think it's a good, starter tube amp. It's not trying to be anything more than what it is, which is a slightly novel desktop tube amplifier with a sleek and minimalist design that will fit in nearly anywhere. The 6AD10 tube is an interesting touch, and they're available pretty inexpensively.
Overall, this is a 3/5. It's value matches the price paid for it, and this type of performance is what you get for that price. A great splurge for a person just getting into audio in high school or college, someone who wants a small tube amp for their desk and wouldn't mind having someone ask about it, someone who likes oddball tube amps, or who just wants something a little different.
The Fisher 400 is a very well engineered, and very collectible, vintage stereo receiver with an iconic champagne faceplate and prominent bank of controls. This one came through the shop after being stored in a garage attic on Camano Island for more than a few years, but somehow managed to be in good overall shape with just some minor corrosion.
This one has all the original Fisher tubes still installed.
Underneath, there's an awful lot going on, but it's laid out pretty cleanly and accessibly. There's not a lot of extra room under the chassis, but it doesn't feel cramped either. Everything has a place.
It doesn't feel cramped for most of the signal components, but there are quite a few capacitors mounted in large cans and it's a challenge to fit them all into the available spaces with solid, safe connections. The cans on this chassis are very difficult to remove, unlike the Scott cans from the same era, so it's more effective to add capacitors below the chassis. In this case all long-life Nichicon electrolytic capacitors.
Replaced the original, leaky rectifier diodes with new 1N4007s.
A printed schematic snip makes a great shop aid. This was taken part way through rebuilding the power supplies.
All in all, five or six new terminal strips were added and capacitors layered across one another at right angles. All of these are Nichicon electrolytic capacitors, with the B+ filter capacitors being 10,000-hour long lifetime models, and the other bulk capacitors being de-rated 5,000- or 8,000-hour lifetime models. It should be quite a while before the power supply section of this amplifier has a failure.
After replacing the electrolytic and paper capacitors, it was time for the first power-up. The 7868 output tubes can be problematic, so for the first power-up the output tubes were removed. Probing for signals at the output, only one side was passing a signal through the full chain. Using the scope to trace the signals, the driver/phase inverter 12AX7 was not lighting. The tube tested fine in an external tester, but the socket had no connectivity. The area around it was corroded, so it was obvious the socket needed to be replaced.
With this resolved, signal showed up properly at the grids of all four output tubes. It was time for some final checks and adjustments. First was to dial them back a little bit and add some more safety with the bias, adding about -1V by changing the 1K divider resistor in the bias supply to an 820 Ohm resistor. Then, double-checking the bias voltage was present on all of the grids. Since this amplifier uses fixed bias, there's no bias pots to adjust here.
After the first power-up, it definitely did pass a signal all the way through, but it sounded really, really bad. The obvious culprits were the ceramic capacitors which were still a part of the original audio signal chain. Many seemed to have cracked bodies around the leads, and it seemed likely this could lead to internal failures. All the ceramic caps in the audio signal path were replaced with film capacitors.
Much, much better. Sounds great, in fact! Some control cleaner in the pots and switches took out the last bit of crackling on audio inputs.
The dial scale in the Fisher 400 is edge-lit by two 6.3V fuse lamps. One was burnt out, and the other just wasn't very bright, you couldn't really tell when it was on. Both were replaced with new LED fuse lamps which should have a very, very long lifespan.
With the audio amplifier sorted, it was time to move on to the FM receiver, which wasn't receiving anything. Injecting the IF signal into the primary of the first IF transformer did produce a signal, but nothing made it from the antenna through the front end.
Both the 6HA5 RF amplifier and 6BA4 oscillator/mixer tubes had no emissions and were replaced, which brought the FM receiver to life immediately, and with the dial scale nearly perfectly tracking already.
Initially received THD on FM was pretty good to start, too. Not too far off from the 0.3% THD over FM. It was really just a matter of touching up.
With these and many more alignment adjustments, on a strong and clear station, received THD settled at 0.22%. Not bad.
The IF chain, front end, and stereo MPX needed only very minor adjustments. The radio sounds fantastic on strong and clear stations, but weaker stations quickly picked up high frequency noise. There are two separate high filters, one in the FM receiver itself, and one in the audio amplifier's tone controls to help address this situation but ultimately this is a receiver that benefits strongly from a top quality antenna.
Quite a few parts came out of this Fisher 400 to make it fully functional again, but now it's in top condition and sounds great!
This Bose® 901 Active Equalizer, Series VI, came into the shop recently. These are some of the most recently produced Active Equalizers, although they're still potentially a few decades old at this point in time. This is only the second Series VI that's come in for repairs to Rain City Audio. The owner reported it was intermittently crackling after playing for a while.
After all new caps and new op-amp chips, this one sounds great!
It's pretty, but this 12BA6 tube has amplified for the last time. Vacuum failure has led to a gas intruding into the vacuum, and it makes a great light show when it's being tested!
As cool as it looks, this would cause some significant damage in a radio if it were operated that way.
This Bose® 901 Series II Active Equalizer, #65097, just came through the shop for an overhaul. It worked briefly, but failed quickly on its original components. Nothing that an overhaul can't take care of!
This particular unit had its three main power supply capacitors replaced, but the rest was all original.
After all new components, upgraded output capacitors, and a thorough cleaning and testing session, this Active Equalizer works and sounds great!


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Ferrar Fenton Bible
Charles Fillmore repeatedly referenced the Ferrar Fenton translation of the Bible. Perhaps the most unique and striking translation is Fenton's translation of the Lord's Prayer, which was referenced by Charles and Cora in the Forward to Teach Us To Pray.
I have decided to set up a framework here for transcribing the PDF files into searchable text. The files that were originally downloaded from the Internet were not searchable. The ones you may download here are searchable, which means you can copy and paste the text into a word processor or text editor.
To the right you will see links to individual chapters of the Bible. The goal is for these links to become active when a chapter has been transcribed. That makes the text easy to read for your fellow metaphysical Bible students and also allows Google to make the text searchable. You can contribute to achieving this goal by translating a chapter or perhaps an entire book of the Bible.
Transcribing begins by sending me an email. I will send you a text file for the book that you wish to transcribe. You then download the PDF and edit the text file so that it is free from any typographical errors. Send to me via email the cleaned text in the body of the email and I will format the chapters and upload them to the website. What I need is plain, clean text. Place a single space between sentences and a single line between paragraphs. Place the footnotes at the bottom of the page with a new line for each note. Don't do any formatting -- no italics, no underlining -- just clean, plain text that is free from typos. Let me know if you can help and I'll email you a sample of what is needed.
Thank you so much for helping the metaphysical Christian community take back the Bible!
Download a PDF of Farrar Fenton's Bible:
Genesis Exodus Leviticus Numbers Deuteronomy Joshua Judges I Samuel II Samuel I Kings II Kings Isaiah Jeremiah Ezekiel Hosea Joel Amos Obadiah Jonah Mikah Nahum Habakuk Zephaniah Hagai Zakariah Malaki Psalms Proverbs Job Song of Solomon Ruth Lamentations Ecclesiastes Esther Daniel Ezra Nehemiah I Chronicles II Chronicles John I John Matthew Mark Luke Acts Romans I Corinthians II Corinthians Galatians Ephesians Philippians Colossians I Thessalonians II Thessalonians I Timothy II Timothy Titus Philemon Hebrews James I Peter II Peter II John III John Jude Revelation
Who Transcribed these pages?
These pages were transcribed between December 2014 and (still ongoing) by these volunteers:
Mark Hicks - Matthew
JT Atkinson - John 1,2,3,4,5,6,7,8,9,10
Preface to the Five Books of Moses
TO MY READERS.
THE very favourable reception given by the most eminent Scholars, Divines, and the general Public, to my translations of St. Paul's Epistles, the New Testament, and the Book of Job into Modern English, has removed all need for my making any apology for this First Volume of The Bible in Modern English, containing the Five Books of Moses. The sale of the preceding portions has been extensive, St. Paul's Epistles having reached a Sixth Edition, the Gospels two large issues, one of 3,000 and the second of 6,000 copies, and the Book of Job two editions.
In the Books of Moses now presented I have followed my plan of making a translation direct from the Hebrew into English without any other version before me. I do not consequently claim my work to be free from error, the more so as, owing to the severe illness of a very learned friend who had intended to revise it, I have had to make the translation single-handed, and not with the valuable assistance he gave me in my former portions of the Sacred Scriptures. The loss of his help, however, has been partially supplied by the aid of that ripe Hebrew Scholar, the Rev. John Bowen, B.D., Rector of St. Lawrence, Wolfs Castle, Pembrokeshire, whose critical knowledge of Oriental tongues, and all the Authorities upon Hebrew, has been of vital assistance to me, especially in the Books of Genesis and Deuteronomy.
But in so entirely a new plan of Translation and Criticism as I have adopted many errors will no doubt be found, and if my readers will point out to me any parts where errors or omission of words may be discovered, I shall be grateful, and record them in my interleaved copy for a future edition.
I am now old; but in my youth I pledged a resolve to God to use my talents and acquirements to establish the authenticity of the Sacred Scriptures as a Revelation from Him to Man, by making them intelligible, through the use of Modern English, to my Countrymen in all parts of the earth; and although I have been engaged in active commercial affairs for over forty years, I never ceased my studies to that end, and the progressive execution of it, in spite of conducting a business that extended to all parts of the world. The Almighty has blessed my work so far, and I hope will enable me to accomplish the whole, and enjoy the pleasure of attaining the chief object of my existence,—to make the Books of the Bible as intelligible to my Race in the British Empire, and the great American Commonwealth, in spoken English, as they are to myself in the Oriental tongues, in return for His inspiration, through those Sacred Scriptures, having in early manhood taken me from the Mental Hell of Sceptical Doubt, to the Home of assured Rest in a knowledge of His Eternal Laws, which He revealed first in them, and is again in our days confirming by His fresh Revelation of them through thesciencesofPhysicalResearch. Upon this fact the reader should consult my Introduction to St. Paul's Epistles, in their sixth edition. 1
Finally, I must note as to my spelling of the proper names of localities and men. As I made my translation from the Hebrew without any English version open before me, I have followed the now general plan of Oriental scholars, and simply transliterated those names, except a few, such as "Moses," "Joshua," etc., which are too fixed by popular use to be altered. The Geographical Names I invariably retain in transliterated form; because the attempt of my predecessors in translation from the Septuagint and Vulgate, and their versionists, to render them into their supposed Greek equivalents territorially, has made such wild misplacing of Nations and Towns as to remind one of the dreams of a mapmaker gone mad; whole kingdoms often having been put thousands of miles away from their actual localities and these blunders have been incorporated in all our literature.
Hoping for the Divine blessing on my work, I remain, My Readers' servant,
FERRAR FENTON.
345, City Road, London, E.C., England, 1901.
Published by Horace Marshall & Son,Temple House,E.C.
TOC Ferrar Fenton Bible
Greyed out links below are not yet transcribed.
Go to the Farrar Fenton Bible homepage for downloading the original PDF and for helping transcribing these pages.
John 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
I John 1 2 3 4 5
Matthew 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Mark 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Luke 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Acts 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Romans 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
I Corinthians 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
II Corinthians 1 2 3 4 5 6 7 8 9 10 11 12 13
Galatians 1 2 3 4 5 6
Ephesians 1 2 3 4 5 6
Philippians 1 2 3 4
Colossians 1 2 3 4
I Thessalonians 1 2 3 4 5
II Thessalonians 1 2 3
I Timothy 1 2 3 4 5 6
II Timothy 1 2 3 4
Titus 1 2 3
Philemon 1
Hebrews 1 2 3 4 5 6 7 8 9 10 11 12 13
James 1 2 3 4 5
I Peter 1 2 3 4 5
II Peter 1 2 3
II John 1
III John 1
Revelation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
The Five Books of Moses
Genesis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
Exodus 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Leviticus 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Numbers 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Deuteronomy 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
The History of the People of Israel
Joshua 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Judges 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
I Samuel 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
II Samuel 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
I Kings 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
II Kings 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
The Books of the Prophets
Isaiah 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66
Jeremiah 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52
Ezekiel 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
Hosea 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Joel 1 2 3 4
Amos 1 2 3 4 5 6 7 8 9
Obadiah 1
Jonah 1 2 3 4
Micah 1 2 3 4 5 6 7
Nahum 1 2 3
Habakuk 1 2 3
Zephaniah 1 2 3
Haggai 1 2
Zakariah 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Malaki 1 2 3 4
The Psalms, Solomon and Sacred Writers
Psalms 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150
Proverbs of Solomon 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Job 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Song of Solomon 1 2 3 4 5 6 7 8
Ruth 1 2 3 4
Lamentations 1 2 3 4 5
Ecclesiastes 1 2 3 4 5 6 7 8 9 10 11 12
Esther 1 2 3 4 5 6 7 8 9 10
Daniel 1 2 3 4 5 6 7 8 9 10 11 12
Ezra 1 2 3 4 5 6 7 8 9 10
Nehemiah 1 2 3 4 5 6 7 8 9 10 11 12 13
I Chronicles 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
II Chronicles 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

redpajama_set_name: RedPajamaCommonCrawl


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You are here: Home / Human Interest / Volunteers to work on Little Sioux Boy Scout Camp
Volunteers to work on Little Sioux Boy Scout Camp
September 1, 2009 By Radio Iowa Contributor
As many as a thousand volunteers will be tackling dozens of chores, big and small, this week at the Little Sioux Boy Scout Camp in western Iowa. Four scouts were killed, dozens hurt, when a tornado hit the camp in June of 2008. Jeff Parness, spokesman for the New York Says Thank You Foundation, says his team will be in Harrison County on Thursday through Sunday.
"We're going to be bringing our largest group ever to the Little Sioux Scout Camp in western Iowa that, obviously, folks know was hit by this deadly tornado a year ago," Parness says. "We're going to help rebuild the camp." Three of the Boy Scouts who died in the storm were Nebraskans, all from Omaha; the fourth boy was Aaron Eilerts of Eagle Grove, Iowa.
Hundreds of trees were toppled in the storm and several camp buildings were flattened. Parness says the volunteers will be building a chapel on the site of the lodge where the four boys were killed using lumber from those trees. He explains their motivation for coming to Iowa.
Parness says, "After Nine Eleven, in the days and weeks that followed, we had so much support from people all around the United States, folks from Iowa, Nebraska, South Dakota, just all across America who poured into New York to help us, that our foundation was formed to honor all of that generosity and to pay it forward." He says it's an amazing team that continues to grow. They're joined by disaster survivors from all communities around the U.S. that they helped on previous anniversaries of Nine Eleven.
Parness says, "Every year, on the Nine Eleven anniversary, we send volunteers from New York to help rebuild communities hit by disaster as our way of saying thank you and celebrating the kindliness and neighborliness and humanity that we experienced not just as New Yorkers, but as a nation, and not just on Nine Eleven but on Nine Twelve."
Story by Pat Powers, KQWC, Webster City
Filed Under: Human Interest


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Phyllis says she feels amazing since being adjusted by Dr. Jamie Cramer. She is never in pain. She is able to function like a normal person. Because of NUCCA, Phyllis was able to cancel her shoulder surgery appointment after her first adjustment.
Everyone was very friendly and welcoming and everything was explained very well. I had a very good first visit.
Glad I heard about you on wmuz,103.5 fm radio.
After my first adjustment I felt relief that I have not received from any other chiropractor and it was the most gentle procedure. Thank you Dr. Cramer and staff!!!
After visiting once for a consult and the first adjustment, I am thrilled and can't wait to go again. Highly recommend!
Very professional and courteous staff. Very positive experience. Looking forward to my next appointment.
Very nice staff and very welcoming.
I was very pleased with my experience so far, and I am looking forward to working with everyone at Precise Chiropractic. Very kind & professional.
The Staff were very informative, and attentive to my concerns. The doctor was very knowledgeable and on point with everything! I limped in, and walked out straighter.
Great staff! Excellent customer service.