Upregulation of SOX9 inhibited IL-1β-induced inflammatory response via increasing the level Smad3 in human chondrocytes and exhibited therapeutic effect on surgically induced OA mice in vivo.
These results suggest that miR-302b suppression may function as a protector in suppressing the inflammation during the development and progression of OA by up-regulating the target Smad3 expression.
The unfolded protein response and the protein characteristic of OA pathology, such as transforming growth factor β, SMAD family member 3, and hypoxia-inducible factor 2α of OA chondrocytes, were also detected by western blotting.
Results suggested the involvement of SMAD family member 3 (<i>SMAD3</i>) and Wnt family member 5A (<i>WNT5A</i>) in the growth of blood vessels and cell aggregation, representing features of cartilage damage in OA.
And the pooled results revealed significant association between SMAD3rs12901499 polymorphism and both knee and hip OA (knee OA: OR 1.18, 95% CI 1.04-1.34; hip OA: OR 1.31, 95% CI 1.18-1.44).
Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.
A SMAD3 mutation has been linked to aneurysm-osteoarthritis syndrome and has been identified as a cause of familial thoracic aortic aneurysm and dissection.
We found that the level of miR-216b was significantly higher and Smad3 expression was obviously lower in OA cartilage and IL-1β-induced chondrocytes than in normal tissues and cells.
Using real-time PCR, the expression of miR-16-5p and SMAD3 in cartilage specimens was determined in 10 patients with knee OA and in 10 traumatic amputees (control).
The TT genotype and T allele of SMAD3rs12102171 polymorphism were more frequent in case than control groups (P=0.04 in both of two polymorphisms), which increased the risk of OA (OR=3.39, 95% CI=1.03-11.11 and OR=1.64, 95% CI=1.03-2.59).
Our finding expands the mutation spectrum of SMAD3 gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype and SMAD3 mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.
Our goal was to establish whether single nucleotide polymorphisms (SNPs) of TGF-β1, TGF-βRI, Smad3 and tissue inhibitor of metalloproteinases 3 (TIMP3), and their interactions, are associated with knee OA.
The expression of TGFB1, SMAD3, and MMP13 were on average 70%, 46%, and 355% higher, respectively, whereas the expression of BMP2 was 88% lower, in OA-affected cartilage than that of controls (all p < 0.03), but no difference was observed between hip and knee OA (all p > 0.4).
SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth.
This G allele was underrepresented in osteoarthritis cases vs controls (P = 0.027, odds ratio = 0.921). rs8031440 is in perfect linkage disequilibrium with five other SMAD3 3'UTR SNPs and our luciferase analysis identified rs3743342 and rs12595334 as being functional.
Our data indicated that genetic variation in the SMAD3 gene is involved in pathogenesis of both knee OA and hand OA in Northeast Chinese population, which is consistent with in European populations.
Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal-dominant syndrome characterized by arterial aneurysms, tortuosity, and aortic dissections in combination with osteoarthritis.
Recently, mutations in the SMAD3 gene were found to cause a new autosomal dominant aneurysm condition similar to Loeys-Dietz syndrome (LDS), mostly with osteoarthritis, called aneurysms-osteoarthritis syndrome (AOS).
This is the first study to provide evidence of a regulatory mechanism of miR-140 independent of WWP2, and new and differential roles for NFAT3 and SMAD3 in the OA process in the regulation of miR-140 transcription.