Wnt signaling and osteoarthritis

Luyten, Frank P.; Tylzanowski, Przemko; Lories, Rik

doi:10.1016/j.bone.2008.12.006

Cited by 148 publications

(116 citation statements)

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“…In human and murine OA, increased protein levels of beta-catenin have been found in degenerated cartilage and osteophyte samples 33 . As shown in mice, the bone-resorption pattern of rheumatoid arthritis was reversed to the bone-forming pattern of osteoarthritis by inhibiting Dickkopf-1 (Dkk-1), a negative regulatory molecule of the canonical Wnt pathway 34 .…”

Section: Developmental Signaling Pathways In the Pathophysiology Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

293

340

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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

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Section: Developmental Signaling Pathways In the Pathophysiology Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

293

340

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“…Although the specific differentiation process in the growth plate and articular cartilage are different, common signaling pathways, such as the Wnt cascades, are involved (26). Interestingly the association between the DOT1L genetic variant and cartilage thickness was present also in people without OA.…”

Section: Discussionmentioning

confidence: 98%

Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

Betancourt

Cailotto

Kerkhof

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW ( P = 4.8 × 10 −10 ). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10 −11 . The SNP was also strongly associated with a 12% reduced risk for HOA ( P = 1 × 10 −4 ). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.

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“…ANP32A has been shown to enhance caspase 9 and caspase 3 activation, thus inducing apoptosis (25). These known effects of the ANP32A gene product suggest that variation in this gene could play a role in increased chondrocyte apoptosis, and, given the importance of Wnt signaling in cartilage metabolism in mouse models (14), in cartilage and bone biology as well (26). The abundant expression of ANP32A in chondrocytes from OA patients and the genetic association of this gene with hip OA that we found suggest that this molecule could indeed play a relevant role in the pathogenesis of OA.…”

Section: Discussionmentioning

confidence: 99%