Session Title: Biology and Pathology of Bone and Joint
Session Type: Abstract Submissions (ACR)
Background/Purpose: Although many osteoarthritis (OA) patients show significant synovial involvement, consequences are largely unknown. We found highly increased expression of canonical Wnts 2b and 16 and Wnt-1-induced secreted protein 1 (WISP1), a downstream protein, in knee joints in two experimental murine OA models. Wnt signaling has been implicated in OA incidence and modulation of the β-catenin pathway leads to OA-like changes in cartilage. In addition, TGF-β signaling is critical in cartilage maintenance. TGF-β signals via both ALK5 and ALK1, resulting in Smad 2/3 and Smad 1/5/8 phosphorylation respectively. In the present study we investigated the potency of canonical Wnts, produced by synovial cells, to induce early OA-like cartilage damage and whether canonical Wnts skew TGF-β signaling from the protective Smad 2/3 pathway to the chondrocyte hypertrophy-inducing Smad 1/5/8 pathway.
Methods: Experimental OA was induced by intra-articular injection of collagenase. Pathway analysis of microarray data was done using DAVID software. Detection of Smad 2/3 and Smad 1/5/8 phosphorylation was done by Western blot analysis. In vivosynovial overexpression of genes from the canonical Wnt signaling pathway was achieved by intra-articular injection of adenoviral vectors. Joint pathology was assessed by histology. Gene expression was analyzed by qPCR.
Results: Pathway analysis showed that both the Wnt and TGF-β signaling pathway were enriched in the synovium of mice with collagenase-induced OA. To determine if synovial overexpression of canonical Wnts leads to cartilage damage, adenoviral vectors for Wnts 8a and 16 were injected into murine knee joints. A significant increase in the incidence of early OA-like lesions at the medial margin of the medial tibial plateau was found 7 days after overexpression. The incidence was 92% (n=12) for Wnt8a overexpression compared to 17% (n=12) for the control virus and 80% (n=5) for Wnt16 overexpression, but only 20% (n=5) for the control virus. Because of their relatively small size, Wnts and WISP1 can enter the cartilage and possibly alter the chondrocyte phenotype. Synovial overexpression of Wnt8a and Wnt16 resulted in β-catenin accumulation in chondrocytes, a tell-tale sign of canonical Wnt signaling, indicating migration of Wnts to the cartilage. Moreover, pre-incubation with Wnt3a or WISP alone or Wnt3a + WISP1 together resulted in decreased TGF-β-induced phosphorylation of Smad 2/3, whereas phosphorylation of Smad 1/5/8 was increased in vitro. This implies a shift towards dominant TGF-β signaling via the hypertrophy-inducing ALK1 pathway. In addition, the expression of the anti-hypertrophic factor Sox9 was decreased after pre-incubation with Wnt3a and WISP1.
Conclusion: Canonical Wnts produced in the synovium may play an important role in OA pathology by inducing β-catenin signaling in the cartilage followed by cartilage damage. Increased expression of canonical Wnts in the synovium, as found in experimental OA, may lead to a phenotype change in articular chondrocytes, probably via modulation of the TGF-β signaling pathway, which is crucial for cartilage homeostasis. This underlines that synovial Wnt/WISP1 expression may be a potential target for OA therapy.
M. H. van den Bosch,
A. B. Blom,
P. L. van Lent,
H. M. van Beuningen,
F. A. van de Loo,
E. N. Blaney Davidson,
P. M. van der Kraan,
W. B. van den Berg,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/synovial-overexpression-of-wnt-and-wnt-1-induced-secreted-protein-1-induces-cartilage-damage-by-skewing-of-tgf-beta-signaling-and-reduction-of-the-anti-hypertrophy-factor-sox9/