ArticleArthritis and rheumatism2012
Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis.
Article in Arthritis and rheumatism, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 1 of them a synthesis that pooled it.
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Who cites it
90 citing papers in PubMed, 1 synthesis or guideline pooled it, 140 citations in OpenAlex.
- Association between the polymorphisms of CALM1 gene and osteoarthritis risk: a meta-analysis based on observational studies.Bioscience reports · 2018Pooled it
- Ice Templated PEG-Alginate Double-Network Cryogels with Tunable Mechanics and Degradation for Soft Tissue Engineering.Gels (Basel, Switzerland) · 2026Article
- Molecular Mechanisms of Chondrocyte Hypertrophy Mediated by Physical Cues and Therapeutic Strategies in Osteoarthritis.International journal of molecular sciences · 2026Review
- Intra-articular delivery of Si-Vangl2 limits cartilage degeneration in an osteoarthritis rat model.Frontiers in bioengineering and biotechnology · 2026Article
- Extracorporeal Shock Wave Therapy in Knee Osteoarthritis: A Mechanistic Narrative Review of Neurogenic Inflammation and the MMP/ADAMTS Axis.International journal of general medicine · 2026Review
- Latent TGF-β content of articular cartilage with development and age.Connective tissue research · 2026Article
- Boolean Networks with Classic and New Updating Modes Applied to Genetic Regulation in Some Familial Diseases.International journal of molecular sciences · 2025Article
- Characterizing the Long Non-Coding RNA Profile of Endometrial Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Anti-Inflammatory Role in Osteoarthritis.International journal of molecular sciences · 2025Article
- Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model.Nature communications · 2025Article
- Eosinophils-Induced Lumican Secretion by Synovial Fibroblasts Alleviates Cartilage Degradation via the TGF-β Pathway Mediated by Anxa1 Binding.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- FHL2 deteriorates IL-1β induced inflammation, apoptosis, and extracellular matrix degradation in chondrocyte-like ATDC5 cells by mTOR and NF-ĸB pathways.BMC musculoskeletal disorders · 2025Article
- TGF-β Enhances Phosphate-Driven Calcification of Human OA Articular Chondrocytes.Calcified tissue international · 2025Article
- Regulation of Skeletal Development and Maintenance by Runx2 and Sp7.International journal of molecular sciences · 2024Review
- Progress and Challenges of Topical Delivery Technologies Meditated Drug Therapy for Osteoarthritis.International journal of nanomedicine · 2024Review
- Loss of miR-204 and miR-211 shifts osteochondral balance and causes temporomandibular joint osteoarthritis.Journal of cellular physiology · 2023Article
- Synergistic roles of CBX4 chromo and SIM domains in regulating senescence of primary human osteoarthritic chondrocytes.Arthritis research & therapy · 2023Article
- Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity.Cell stem cell · 2023Article
- Computational and experimental characterizations of the spatiotemporal activity and functional role of TGF-β in the synovial joint.Journal of biomechanics · 2023Article
- Natural compounds protect against the pathogenesis of osteoarthritis by mediating the NRF2/ARE signaling.Frontiers in pharmacology · 2023Review
- Identification of membrane proteins regulated by ADAM15 by SUSPECS proteomics.Frontiers in molecular biosciences · 2023Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
objectiveTo identify mechanisms by which Smad3 maintains articular cartilage and prevents osteoarthritis.
methodsA combination of in vivo and in vitro approaches was used to test the hypothesis that Smad3 represses Runx2-inducible gene expression to prevent articular cartilage degeneration. Col2-Cre;Smad3(fl/fl) mice allowed study of the chondrocyte-intrinsic role of Smad3 independently of its role in the perichondrium or other tissues. Primary articular cartilage chondrocytes from Smad3(fl/fl) mice and ATDC5 chondroprogenitor cells were used to evaluate Smad3 and Runx2 regulation of matrix metalloproteinase 13 (MMP-13) messenger RNA (mRNA) and protein expression.
resultsChondrocyte-specific reduction of Smad3 caused progressive articular cartilage degeneration due to imbalanced cartilage matrix synthesis and degradation. In addition to reduced type II collagen mRNA expression, articular cartilage from Col2-Cre;Smad3(fl/fl) mice was severely deficient in type II collagen and aggrecan protein due to excessive MMP-13-mediated proteolysis of these key cartilage matrix constituents. Normally, transforming growth factor β (TGFβ) signals through Smad3 to confer a rapid and dynamic repression of Runx2-inducible MMP-13 expression. However, we found that in the absence of Smad3, TGFβ signals through p38 and Runx2 to induce MMP-13 expression.
conclusionOur findings elucidate a mechanism by which Smad3 mutations in humans and mice cause cartilage degeneration and osteoarthritis. Specifically, Smad3 maintains the balance between cartilage matrix synthesis and degradation by inducing type II collagen expression and repressing Runx2-inducible MMP-13 expression. Selective activation of TGFβ signaling through Smad3, rather than p38, may help to restore the balance between matrix synthesis and proteolysis that is lost in osteoarthritis.
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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.