ArticleThe Journal of experimental medicine2020
Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway.
Article in The Journal of experimental medicine, 2020. 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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26 citing papers in PubMed, 44 citations in OpenAlex.
- In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.Aging cell · 2026Article
- The pathogenesis and intersecting mechanisms of monogenic bone mass disorders.Nature reviews. Endocrinology · 2026Review
- MFAP4 Promotes Scar Formation by Regulating Macrophage-Myofibroblast Transformation Through Activation of the TGF-β/Smad3 Signalling Pathway.Experimental dermatology · 2026Article
- ZMAT1 Promotes Osteoclastogenesis Through TRIM46 Mediated YAP1 Degradation and Inhibits Osteoblastogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Recent advances in TGF-β signaling: insights into regulation, pathophysiological function, and clinical translation.Cell regeneration (London, England) · 2026Article
- Downregulated Smad3 signaling impairs the maturation of MO-MDSC in colorectal cancer.Cell death & disease · 2025Article
- Melorheostosis: Clinical, radiological, and histopathological features with a literature review.Physiological reports · 2025Review
- Novel mutations of SRPX facilitate the stemness and malignant progression of glioma.British journal of cancer · 2025Article
- Developing a standard dataset in the European registries for rare endocrine and bone conditions-a Melorheostosis dataset.Orphanet journal of rare diseases · 2025Article
- Unraveling melorheostosis: insights into clinical features, diagnosis, and treatment.JBMR plus · 2025Review
- Article
- Principles of clinical genetics for rheumatologists: clinical indications and interpretation of broad-based genetic testing.Advances in rheumatology (London, England) · 2024Review
- p-Smad3 differentially regulates the cytological behavior of osteoclasts before and after osteoblasts maturation.Molecular biology reports · 2024Article
- The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease.Cell research · 2024Review
- Melorheostosis: A Review of the Literature and a Case Report.Medicina (Kaunas, Lithuania) · 2023Review
- High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Review
- Article
- Clinical characteristics of 10 Chinese patients with melorheostosis and identification of a somatic MAP2K1 variant in one case.Molecular genetics & genomic medicine · 2022Article
- Advances in single-cell sequencing and its application to musculoskeletal system research.Cell proliferation · 2022Review
- Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source.Calcified tissue international · 2021Article
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17 authors at 3 institutions in 2 countries.
Funding
Abstract
Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-β/SMAD3 activation by BMP signaling in SMAD3 mutation-positive endosteal melorheostosis, which may guide future therapies.
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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.