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The SMAD3 gene codes for the 425 amino acid zinc binding mothers against decapentaplegic homolog 3. The mothers against decapentaplegic homolog 3/mothers against decapentaplegic homolog 4 (SMAD3/SMAD4) complex is a key transcription regulator. it is an intracellular signal transducer and transcriptional modulator activated by TGF-β and activin type 1 receptor kinases. Mothers against decapentaplegic homolog 3 binds the tet response element in the promoter region of many genes that are regulated by TGF-β. On formation of the SMAD3/SMAD4 complex, it activates transcription. It can also form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Mothers against decapentaplegic homolog 3 has an inhibitory hormone-sensitive effect on wound healing . It modulates chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Melatonin down regulates SMAD3 which has been shown to suppress some cancers[1]. [SMAD3]] activity is also likely to be relevant to some tissue fibrosis and again melatonin acting through SMAD3 might have beneficial effects in cardiac or pulmonary fibrosis. Mutations of SMAD3 lead to:

  1. Loeys-Dietz syndrome 3 (LDS3, OMIM:613795)
    • An aortic aneurysm and dissection syndrome with widespread systemic involvement. The triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate is found in Loeys-Dietz syndrome which is also associated with early-onset osteoarthritis.
  2. colorectal cancer (OMIM:114500)

Variations in SMAD3 affect the risk of osteoarthritis.


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