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.
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.
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.
SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth.
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.
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.
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.
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).
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.
IL-1beta or TNF-alpha exerted a suppressive effect on Smad3/4 DNA-binding activity in human articular chondrocytes, as well as on TGF-beta-induced stimulation of Smad3/4 DNA-binding activity and Smad2/3 phosphorylation in human OA and bovine articular chondrocytes.
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).
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).
AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis.
A SMAD3 mutation has been linked to aneurysm-osteoarthritis syndrome and has been identified as a cause of familial thoracic aortic aneurysm and dissection.