The interaction of canonical bone morphogenetic protein- and Wnt-signaling pathways may play an important role in regulating cartilage degradation in osteoarthritis

Bone morphogenetic proteins (BMPs) and Wnts are important signaling protein families with key roles in embryologic, patterning, development, and tissue remodeling in growth. BMP and Wnt-β-catenin are highly evolutionarily conserved pathways that, though often regulating similar cellular events, are independent signaling mechanisms that can have complementary or antagonistic effects depending on various factors, including cell type and developmental stage. Although BMP and Wnt-β-catenin have the ability to act entirely independently, there is a developing body of evidence for specific extra- and intra-cellular molecular interactions and crosstalk that occur between BMP and Wnt-β-catenin signaling and that again this may be cell type-specific. In the previous issue of Arthritis Research & Therapy, Papathanasiou and colleagues provide novel insights into the role and direct interaction of BMP2 and canonical Wnt-β-catenin signaling in regulating chondrocyte hypertrophy and matrix metalloproteinase/a disintegrin like and metalloproteinase with thrombospondin type I motif (MMP/ADAMTS) synthesis in osteoarthritis.

signaling in regulating chondrocyte hypertrophy and matrix metalloproteinase (MMP)/aggrecanolytic ADAMTS (a disintegrin like and metalloproteinase with thrombospondin type I motif) synthesis in osteoarthritis (OA). OA is the most common cause of joint pain and disability, and with increasing age and obesity of the population, the already major socioeconomic importance will continue to increase. Currently, in most Western cultures, OA affl icts more than 10% of the entire population and over a third of those over 65; an estimated 25 to 30 million people in the US suff er from this disease. Th e central pathological feature of OA is often considered to be the progressive destruction of articular cartilage that normally provides the load-bearing surface in the joint. Much has been learned in recent years about the mechanisms that drive cartilage matrix breakdown and loss in OA, and chondrocyte-derived metalloproteinases, particularly the ADAMTS and collagenolytic MMPs, have a key role. It is evident that a phenotypic shift in the mature articular chondrocyte to a cell type that displays many characteristics typical of hypertrophic cells in the lower zones of the growth plate is a typical feature of OA and is associated with the progressive cartilage breakdown observed (reviewed in [2]). Less clearly understood are the specifi c signaling pathways involved in regulating the chondrocyte phenotype, how they interact, and whether this changes in health and in diseases such as OA.
BMPs and Wnts are important signaling protein families with key roles in embryologic, patterning, develop ment, and tissue remodeling in growth. BMP and Wnt-β-catenin are highly evolutionarily conserved pathways that, though often regulating similar cellular events, are independent signaling mechanisms that can have complementary or antagonistic eff ects depending on various factors, including cell type and developmental stage (reviewed in [3]). Although BMP and Wnt-βcatenin have the ability to act entirely independently,

Abstract
Bone morphogenetic proteins (BMPs) and Wnts are important signaling protein families with key roles in embryologic, patterning, development, and tissue remodeling in growth. BMP and Wnt-β-catenin are highly evolutionarily conserved pathways that, though often regulating similar cellular events, are independent signaling mechanisms that can have complementary or antagonistic eff ects depending on various factors, including cell type and developmental stage. Although BMP and Wnt-β-catenin have the ability to act entirely independently, there is a developing body of evidence for specifi c extra-and intra-cellular molecular interactions and crosstalk that occur between BMP and Wnt-β-catenin signaling and that again this may be cell type-specifi c. In the previous issue of Arthritis Research & Therapy, Papathanasiou and colleagues provide novel insights into the role and direct interaction of BMP2 and canonical Wnt-β-catenin signaling in regulating chondrocyte hypertrophy and matrix metalloproteinase/a disintegrin like and metalloproteinase with thrombospondin type I motif (MMP/ADAMTS) synthesis in osteoarthritis.

© 2010 BioMed Central Ltd
The interaction of canonical bone morphogenetic protein-and Wnt-signaling pathways may play an important role in regulating cartilage degradation in osteoarthritis there is a developing body of evidence for specifi c extraand intra-cellular molecular interactions and crosstalk that occur between BMP and Wnt-β-catenin signaling and that again may be cell type-specifi c [3]. In addition to having a key role in development, BMPs and Wnts are emerging as critical regulators of bone and cartilage homeostasis in the adult and, import antly, in the onset and progression of musculoskeletal diseases.
BMPs are multi-functional growth factors that belong to the transforming growth factor-β super family. Evidence suggests that BMP signaling is mediated primarily through the canonical BMP-Smad pathway in chondrocytes. BMPs bind the type II receptor and phosphorylate type I serine or threonine receptors, which subsequently phosphorylate Smad1, Smad5, and Smad8. BMPs are known to induce human mesenchymal stem cells to diff erentiate into chondrocytes, and BMP2 is a crucial local factor for chondrocyte proliferation and maturation during endochondral ossifi cation [4,5]. In their report, Papathanasiou and colleagues show not only that human end-stage OA chondrocytes produce BMP2 and BMP4 but also, importantly, that BMP2, but not BMP4, can drive expression of low-density lipoprotein receptor 5 (LRP5). LRP5 is one of the most important co-receptors in the canonical Wnt-β-catenin signaling pathway; binding of Wnt ligands to the frizzled/LRP co-receptor complex leads to β-catenin stabilization, nuclear translocation, and activation of target genes.
Th ere is a large body of evidence demonstrating the central role for Wnt signaling in regulating adult bone turnover; increased β-catenin activity inducing bone production and inhibition of soluble antagonists is an emerging therapeutic approach for osteoporotic and infl ammatory bone loss [6,7]. In cartilage, Wnt-β-catenin signaling plays a dual role; activity is essential for chondrocyte proliferation and maintenance of their pheno typic characteristics [8], but excessive activity increases chondrocyte hypertrophy and expression of cartilage degrades metalloproteinases [9]. Th e eff ect may be cell type-specifi c, and Wnt-β-catenin activation is essential for maintenance of the superfi cial zone chondrocyte phenotype and proteoglycan 4 (lubricin) expression [8]. Inhibition of β-catenin rapidly leads to downregulation of lubricin and increased collagen X expression in super fi cial zone chondrocytes. In chondrocytes from human end-stage OA cartilage, activation of canonical Wnt-β-catenin signaling by Wnt-2B and Wnt-16 can drive MMP and aggrecanase production [9]. Understanding the mecha nisms that regulate Wnt signaling in chondrocytes in OA may provide keys to controlling cartilage degradation.
One of the most important fi ndings by Papathanasiou and colleagues is the demonstration of a new and unique function of BMP2 in chondrocytes in acting as a regulator of canonical Wnt-β-catenin signaling. Treatment of both normal and OA primary human chondrocytes with BMP2 for 12 hours enhanced total β-catenin expression while diminishing the degradation of βcatenin (phospho-β-catenin). Th is was accompanied by signifi cant increases in mRNA for key cartilage-degrading enzymes MMP-13 and ADAMTS-5 in concert with a shift toward a hypertrophic chondrocyte phenotype as measured by increased collagen X expression. Th is eff ect was absent in LRP5 small inter fering RNA (siRNA) pretreated chondrocytes and did not occur with BMP4, suggesting the unique function of BMP2 in specifi cally upregulating LRP5 and augmenting Wnt-β-catenin signaling. Th e BMP2-driven increase in LRP5 mRNA was mediated through Smad1/5/8 binding to the LRP5 promoter.
Th e paper by Papathanasiou and colleagues adds to the accumulating evidence that increased or perhaps excessive activation of canonical Wnt-β-catenin signaling in chondrocytes is detrimental and contributes to OA cartilage degradation. Th erapeutic approaches to block or suppress canonical Wnt-β-catenin signaling may protect cartilage damage in end-stage OA. Th ere are many naturally occurring Wnt-β-catenin signaling antago nists, including dickkopf 1 (DKK1), secreted frizzledrelated proteins (sFRPs), and sclerostin (SOST). Evidence suggests that circulating DKK1 levels negatively correlate with biomarkers of cartilage breakdown in patients with OA [10]; sFRP3 knockout mice have augmented cartilage proteoglycan loss in a collagenase-induced instability model of arthritis [11], and co-treatment of SOST with pro-infl ammatory cytokines can attenuate cartilage matrix breakdown [12]. Th e role of SOST is interesting in light of the interaction between BMP2 and Wnt signaling pathways reported by Papathanasiou and colleagues. It appears that SOST can also function as a BMP antagonist in osteoblast and osteocytes by binding intra-cellularly to BMP7 and targeting the growth factor for proteosomal degradation [13]. Th is provides yet another mechanism by which BMP and Wnt signaling pathways may directly interact; it will be interesting to see whether this eff ect of SOST on BMP7 (and possibly other BMPs) also occurs in chondrocytes, particularly in OA, where chondrocyte SOST expression is increased [12].
Th e BMP and Wnt signaling pathways are critical in regulating chondrocytes and maintaining the health and integrity of cartilage matrix. In other cell types/organs such as those in bone, it is the combinatorial integration and complex crosstalk between these two pathways that are emerging as signifi cant regulators of development and tissue homeostasis [3]. Th e fi ndings by Papathanasiou and colleagues suggest that similar signaling pathway inter actions may be important in chondrocytes and could play a role in the development and progression of OA.
A better appreciation of chondrocyte regulatory mechanisms may provide new avenues for development of therapeutic approaches for the treatment of OA.