Fig. 21.4 ). An important signaling pathway that controls remodeling involves three factors: (1) the transmembrane receptor activator of NF-κB (RANK), which is expressed on osteoclast precursors; (2) RANK ligand (RANKL), which is expressed on osteoblasts and marrow stromal cells; and (3) osteoprotegerin (OPG), a secreted “decoy” receptor made by osteoblasts that can block RANK interaction with RANKL. RANK signaling activates the transcription factor NF-κB, which is essential for the generation and survival of osteoclasts. Other important pathways include monocyte-colony stimulating factor (M-CSF), produced by osteoblasts. WNT proteins produced by various cells bind to the LRP5 and LRP6 receptors on osteoblasts and trigger the production of OPG. The importance of these pathways is proven by rare but informative germline mutations in the OPG, RANK, RANKL, and LRP5 genes, which cause severe disturbances of bone metabolism (described later).
Bone resorption or bone formation can be favored by tipping the RANK-to-OPG ratio. Systemic factors that affect this balance include hormones, vitamin D, inflammatory cytokines (e.g., IL-1), and growth factors (e.g., bone morphogenetic factors). The mechanisms are complex, but parathyroid hormone (PTH), IL-1, and glucocorticoids promote osteoclast differentiation and bone turnover. In contrast, BMPs and sex hormones (estrogen, testosterone) generally block osteoclast differentiation or activity by favoring OPG expression.
Peak bone mass is achieved in early adulthood after the cessation of skeletal growth. This set point is determined by many factors, including polymorphisms in the vitamin D and LRP5/6 receptors, nutrition, and physical activity. Beginning in the fourth decade, resorption exceeds formation, resulting in a decline in skeletal mass.
Congenital abnormalities of the skeleton frequently result from inherited mutations and first become manifest
Fig.21.4Paracrinemolecularmechanismsthatregulateosteoclastformationandfunction.Osteoclastsarederivedfromthesamemononuclearcellsthatdifferentiateintomacrophages.Osteoblast/stromalcellmembrane-associatedRANKLbindstoitsreceptorRANKlocatedonthecellsurfaceofosteoclastprecursors.Thisinteractioninthebackgroundofmacrophagecolony-stimulatingfactor(M-CSF)causestheprecursorcellstoproducefunctionalosteoclasts.Stromalcellsalsosecreteosteoprotegerin(OPG),whichactsasa“decoy”receptorforRANKL,preventingitfrombindingtheRANKreceptoronosteoclastprecursors.Consequently,OPGpreventsboneresorptionbyinhibitingosteoclastdifferentiation.
http://ebooksmedicine.net during the early stages of bone formation. The spectrum of developmental disorders of bone is broad, and the classification system is not standardized. Here we will categorize the major diseases according to their perceived pathogenesis.