ArticleThe Journal of clinical investigation2016
Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 56 citations in OpenAlex.
- Association of TCF7L2 and LEPR gene variants (rs7903146 and rs1137101) with primary knee osteoarthritis in a northern Mexican Mestizo population.Clinical rheumatology · 2026Article
- Integrated post-GWAS, single-cell, and functional analyses prioritizeFrontiers in immunology · 2026Article
- Single-cell sequencing reveals a senescent immune landscape in bone marrow lesions inducing articular cartilage damage in osteoarthritis.Bone research · 2025Article
- WNT signaling in cancer: molecular mechanisms and potential therapies.Molecular biomedicine · 2025Review
- Hedgehog Signalling in Osteogenesis and Bone Metabolism: Molecular Mechanisms, Regulatory Networks and Implications for Skeletal Disease.Journal of cellular and molecular medicine · 2025Review
- Signaling pathway mechanisms of circadian clock gene Bmal1 regulating bone and cartilage metabolism: a review.Bone research · 2025Review
- Impact of Different Cell Types on the Osteogenic Differentiation Process of Mesenchymal Stem Cells.Stem cells international · 2025Review
- Role of Pyroptosis in the Pathogenesis of Osteoarthritis: An Updated Review.Journal of inflammation research · 2025Review
- Targeted Therapy of Osteoarthritis via Intra-Articular Delivery of Lipid-Nanoparticle-Encapsulated Recombinant Human FGF18 mRNA.Advanced healthcare materials · 2024Article
- The involvement of signaling pathways in the pathogenesis of osteoarthritis: An update.Journal of orthopaedic translation · 2024Review
- Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy.Journal of hematology & oncology · 2024Review
- Signalling interaction between β-catenin and other signalling molecules during osteoarthritis development.Cell proliferation · 2024Review
- RPL35 downregulated by mechanical overloading promotes chondrocyte senescence and osteoarthritis development via Hedgehog-Gli1 signaling.Journal of orthopaedic translation · 2024Article
- Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms.Cellular and molecular life sciences : CMLS · 2024Article
- WTAP-mediated mExperimental & molecular medicine · 2024Article
- Genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis.American journal of human genetics · 2023Article
- Wnt signaling: Essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders.Genes & diseases · 2023Review
- Osteoarthritis: pathogenic signaling pathways and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- New developments in the biology of fibroblast growth factors.WIREs mechanisms of disease · 2022Review
- Primary Cilia Direct Murine Articular Cartilage Tidemark Patterning Through Hedgehog Signaling and Ambulatory Load.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.