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Hedgehog inhibits ?-catenin activity in synovial joint development and osteoarthritis.

ABSTRACT: Both the WNT/?-catenin and hedgehog signaling pathways are important in the regulation of limb development, chondrocyte differentiation, and degeneration of articular cartilage in osteoarthritis (OA). It is not clear how these signaling pathways interact in interzone cell differentiation and synovial joint morphogenesis. Here, we determined that constitutive activation of hedgehog signaling specifically within interzone cells induces joint morphological changes by selectively inhibiting ?-catenin-induced Fgf18 expression. Stabilization of ?-catenin or treatment with FGF18 rescued hedgehog-induced phenotypes. Hedgehog signaling induced expression of a dominant negative isoform of TCF7L2 (dnTCF7L2) in interzone progeny, which may account for the selective regulation of ?-catenin target genes observed. Knockdown of TCF7L2 isoforms in mouse chondrocytes rescued hedgehog signaling-induced Fgf18 downregulation, while overexpression of the human dnTCF7L2 orthologue (dnTCF4) in human chondrocytes promoted the expression of catabolic enzymes associated with OA. Similarly, expression of dnTCF4 in human chondrocytes positively correlated with the aggrecanase ADAMTS4. Consistent with our developmental findings, activation of ?-catenin also attenuated hedgehog-induced or surgically induced articular cartilage degeneration in mouse models of OA. Thus, our results demonstrate that hedgehog inhibits selective ?-catenin target gene expression to direct interzone progeny fates and articular cartilage development and disease. Moreover, agents that increase ?-catenin activity have the potential to therapeutically attenuate articular cartilage degeneration as part of OA.

SUBMITTER: Rockel JS

PROVIDER: S-EPMC4855923 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis.

Rockel Jason S JS Yu Chunying C Whetstone Heather H Craft April M AM Reilly Katherine K Ma Henry H Tsushima Hidetoshi H Puviindran Vijitha V Al-Jazrawe Mushriq M Keller Gordon M GM Alman Benjamin A BA

The Journal of clinical investigation 20160328 5

Both the WNT/β-catenin and hedgehog signaling pathways are important in the regulation of limb development, chondrocyte differentiation, and degeneration of articular cartilage in osteoarthritis (OA). It is not clear how these signaling pathways interact in interzone cell differentiation and synovial joint morphogenesis. Here, we determined that constitutive activation of hedgehog signaling specifically within interzone cells induces joint morphological changes by selectively inhibiting β-cateni ...[more]

PMID: 27018594

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Project description:BackgroundHMGB1 usually serves as a damage-associated molecular pattern (DAMP) molecule (also known as alarmin) that regulates the inflammatory and immune responses via different receptors or direct uptake. Numerous studies have reported the association between HMGB1 and inflammatory diseases; however, its role in temporomandibular joint (TMJ) osteoarthritis (OA) has not been elucidated. In this retrospective study, we aimed to investigate HMGB1 levels in the synovial fluid (SF) in patients with TMJOA and TMID, their correlation with TMJOA and TMID severity, and the therapeutic effect of sodium hyaluronate (hyaluronic acid, HA) on TMJOA.MethodsSF samples were analyzed for 30 patients with TMJ internal derangement (TMJID) and TMJOA, along with visual analog scale (VAS) scores, radiographic stages, and mandibular functional limitations. The SF levels of HMGB1, IL-1β, IL-18, PGE2, RAGE, TLR4, and iNOS were determined via an enzyme-linked immunosorbent assay. To evaluate the therapeutic effects of HA, pre-treatment and post-treatment clinical symptoms were also compared in patients of the TMJOA group who had received an intra-articular injection of HA.ResultsVAS and Jaw Functional Limitation Scale (JFLS) scores were significantly higher in the TMJOA group than in the TMNID group, as were SF levels of HMGB1, TLR4, IL-1β, IL-18, PGE2, and iNOS. The synovial HMGB1 level was positively correlated with the VAS score (r = 0.5512, p = 0.0016) and mandibular functional limitations (r = 0.4684, p = 0.0054). The cut-off value for the HMGB1 level as a diagnostic biomarker was 986.8 pg/ml. The SF level of HMGB1 yielded an area under the curve value (AUC) of 0.8344 for predicting TMJOA. HA alleviated TMJ disorders by significantly reducing the VAS score and improving the maximum extent of mouth opening in both the TMJID and TMJOA groups (p < 0.05). Moreover, patients in both the TMJID and TMJOA groups exhibited significant improvement in the JFLS score following HA treatment.ConclusionsOur results indicate that HMGB1 is a potential marker for predicting the severity of TMJOA. Intra-articular HA injection exerts a positive therapeutic effect on TMJOA; however, further investigations are warranted to validate its therapeutic effect in the late phase of visco-supplementation treatment.

Dataset Information

Hedgehog inhibits ?-catenin activity in synovial joint development and osteoarthritis.

Publications

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis.

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