Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis
Jason S. Rockel, … , Gordon M. Keller, Benjamin A. Alman
Jason S. Rockel, … , Gordon M. Keller, Benjamin A. Alman
Published March 28, 2016
Citation Information: J Clin Invest. 2016;126(5):1649-1663. https://doi.org/10.1172/JCI80205.
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Research Article Bone biology

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

Abstract

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-catenin–induced Fgf18 expression. Stabilization of β-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 β-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 β-catenin also attenuated hedgehog-induced or surgically induced articular cartilage degeneration in mouse models of OA. Thus, our results demonstrate that hedgehog inhibits selective β-catenin target gene expression to direct interzone progeny fates and articular cartilage development and disease. Moreover, agents that increase β-catenin activity have the potential to therapeutically attenuate articular cartilage degeneration as part of OA.

Authors

Jason S. Rockel, Chunying Yu, Heather Whetstone, April M. Craft, Katherine Reilly, Henry Ma, Hidetoshi Tsushima, Vijitha Puviindran, Mushriq Al-Jazrawe, Gordon M. Keller, Benjamin A. Alman

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Figure 6

Activation of β-catenin in chondrocytes attenuates hedgehog and surgically induced articular cartilage degeneration.

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Activation of β-catenin in chondrocytes attenuates hedgehog and surgical...
(A–D and F–I) Mice were injected with tamoxifen at 8 weeks of age. Hind limbs were collected after 6 weeks and stained with SafO (A–D) or for FGF18 by immunohistochemistry (F–I). (J–R) The medial meniscus of the left knee was surgically removed in 8-week-old mice. Tamoxifen was injected 6 days after surgery, and mice were collected at 7 weeks after surgery. Hind limbs sections were stained with SafO (J–M) or for FGF18 by immunohistochemistry (O–R). (B and K) Black arrowheads indicate zones of cartilage degeneration along the tibial surface. (E and N) Cartilage degeneration severity was graded by OARSI scoring recommended for the mouse. Individual points are an average of 3–8 sections from 2-4 slides separated by a minimum of 60 μm and graded by 3 blinded, independent reviewers. Bars represent mean ± SEM. Data were analyzed by 1-way ANOVA followed by Tukey’s post-hoc tests. Unlabeled bars or bars labeled with the same letter are not significantly different from each other (P > 0.05). n ≥ 6 animals per group. Scale bars: 400 μm (A); 200 μm (F). See also Supplemental Figures 5 and 6 and Supplemental Table 1.