ArticleArthritis and rheumatism2010
Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis.
Article in Arthritis and rheumatism, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 49 citations in OpenAlex.
- ATF-4 deficiency increases ER stress and induces osteoarthritis formation in mice.Molecular and cellular biochemistry · 2025Article
- Intra-articular injection of miRNA-1 agomir, a novel chemically modified miRNA agonists alleviates osteoarthritis (OA) progression by downregulating Indian hedgehog in rats.Scientific reports · 2024Article
- Review
- 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
- Article
- The miR-302c/transforming growth factor-β receptor type-2 axis modulates interleukin-1β-induced degenerative changes in osteoarthritic chondrocytes.Journal of cell communication and signaling · 2022Article
- Protein tyrosine phosphatases in skeletal development and diseases.Bone research · 2022Review
- Unbiased transcriptome mapping and modeling identify candidate genes and compounds of osteoarthritis.Frontiers in pharmacology · 2022Article
- AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis.Frontiers in cell and developmental biology · 2021Review
- The Synovium Attenuates Cartilage Degeneration in KOA through Activation of the Smad2/3-Runx1 Cascade and Chondrogenesis-related miRNAs.Molecular therapy. Nucleic acids · 2020Article
- miR-140 Attenuates the Progression of Early-Stage Osteoarthritis by Retarding Chondrocyte Senescence.Molecular therapy. Nucleic acids · 2020Article
- Molecular Signaling Interactions and Transport at the Osteochondral Interface: A Review.Frontiers in cell and developmental biology · 2020Review
- Review
- Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis.Frontiers in bioengineering and biotechnology · 2018Review
- SMAD3 and SMAD4 have a more dominant role than SMAD2 in TGFβ-induced chondrogenic differentiation of bone marrow-derived mesenchymal stem cells.Scientific reports · 2017Article
- TGF-β regulates phosphorylation and stabilization of Sox9 protein in chondrocytes through p38 and Smad dependent mechanisms.Scientific reports · 2016Article
- Skeletal Characterization of Smurf2-Deficient Mice and In Vitro Analysis of Smurf2-Deficient Chondrocytes.PloS one · 2016Article
- Attenuation of the progression of articular cartilage degeneration by inhibition of TGF-β1 signaling in a mouse model of osteoarthritis.The American journal of pathology · 2015Article
- Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis.BMJ open · 2015Article
- Col2CreER(T2), a mouse model for a chondrocyte-specific and inducible gene deletion.European cells & materials · 2014Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
objectiveTo investigate the biologic significance of Smad3 in the progression of osteoarthritis (OA), the crosstalk between Smad3 and activating transcription factor 2 (ATF-2) in the transforming growth factor beta (TGFbeta) signaling pathway, and the effects of ATF-2 overexpression and p38 activation in chondrocyte differentiation.
methodsJoint disease in Smad3-knockout (Smad3(-/-)) mice was examined by microfocal computed tomography and histologic analysis. Numerous in vitro methods including immunostaining, real-time polymerase chain reaction, Western blotting, an ATF-2 DNA-binding assay, and a p38 kinase activity assay were used to study the various signaling responses and protein interactions underlying the altered chondrocyte phenotype in Smad3(-/-) mice.
resultsIn Smad3(-/-) mice, an end-stage OA phenotype gradually developed. TGFbeta-activated kinase 1 (TAK1)/ATF-2 signaling was disrupted in Smad3(-/-) mouse chondrocytes at the level of p38 MAP kinase (MAPK) activation, resulting in reduced ATF-2 phosphorylation and transcriptional activity. Reintroduction of Smad3 into Smad3(-/-) cells restored the normal p38 response to TGFbeta. Phosphorylated p38 formed a complex with Smad3 by binding to a portion of Smad3 containing both the MAD homology 1 and linker domains. Additionally, Smad3 inhibited the dephosphorylation of p38 by MAPK phosphatase 1 (MKP-1). Both ATF-2 overexpression and p38 activation repressed type X collagen expression in wild-type and Smad3(-/-) chondrocytes. P38 was detected in articular cartilage and perichondrium; articular and sternal chondrocytes expressed p38 isoforms alpha, beta, and gamma, but not delta.
conclusionSmad3 is involved in both the onset and progression of OA. Loss of Smad3 abrogates TAK1/ATF-2 signaling, most likely by disrupting the Smad3-phosphorylated p38 complex, thereby promoting p38 dephosphorylation and inactivation by MKP-1. ATF-2 and p38 activation inhibit chondrocyte hypertrophy. Modulation of p38 isoform activity may provide a new therapeutic approach for OA.
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Registered trials
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.