Understanding how BMP antagonists and counteracting TGFβ signals intersect with Gdf5 to sculpt the joint interzone is essential for understanding the origin of osteoarthritis and other diseases of joint tissues.
Given GDF5 involvement in hip development, and osteoarthritis (OA) and developmental hip dysplasia (DDH) risk, here we sought to assess the role(s) of GDF5 and its regulatory sequence on the development of hip morphology linked to injury risk.
Overall, these results suggest that miR-449a contributes to chondrocyte ECM degradation in OA via directly targeting GDF5, thereby providing insights to a promising therapeutic target for the treatment of human OA.
Stratified analyses based on disease type showed a significant association between the GDF5rs143383 polymorphism and increased risk of IDD and OA under all genetic models studied.
Intra-articular therapy with recombinant human GDF5 arrests disease progression and stimulates cartilage repair in the rat medial meniscus transection (MMT) model of osteoarthritis.
Overall, BMP-14rs143383 polymorphism was negatively correlated with the susceptibility to knee OA and hand OA under genetic contrasts of CC versus TT, CC + TC versus TT, CC versus TT + TC, C versus T, TC versus TT (OR = 0.71, 95% CI = 0.65-0.79; OR = 0.81, 95% CI = 0.73-0.89; OR = 0.79, 95% CI = 0.71-0.86; OR = 0.85, 95% CI = 0.81-0.90; OR = 0.84, 95% CI = 0.75-0.93), and TC versus TT, CC versus TT + TC, C versus T (OR = 0.76, 95% CI = 0.65-0.89; OR = 0.79, 95% CI = 0.68-0.92; OR = 0.90, 95% CI = 0.85-0.95), respectively; similar results were observed in subgroups after stratification analyses.
A functional single nucleotide polymorphism (SNP) +104T/C in the 5'-UTR of GDF5 (rs143383) was reported to be associated with osteoarthritis susceptibility in Han Chinese and Japanese populations.
We observed nominally significant associations (P < 0.05) with 3 previously reported OA loci: rs143383 in GDF5 (OR 1.12 [95% CI 1.04-1.21], P = 2.13 × 10<sup>-3</sup> ), rs835487 in CHST11 (OR 0.93 [95% CI 0.85-0.99], P = 0.03), and rs8044769 in FTO (OR 1.10 [95% CI 1.03-1.19], P = 6.13 × 10<sup>-3</sup> ).
MSCs from healthy donors and OA patients were studied and the effect of GDF5 was assessed by measuring the wet mass of the discs, by histological staining, and by monitoring the change in expression of anabolic, catabolic and hypertrophic protein-coding genes.
The large array of modular enhancers for Gdf5 provide a new foundation for studying the spatial specificity of joint patterning in vertebrates, as well as new candidates for regulatory regions that may also influence osteoarthritis risk in human populations.
Our results demonstrate that SNP rs143383 of GDF5 is a compelling risk factor for both knee and hand OA, and provide further support for GDF5 in the etiology of OA.
This may be a cause or a consequence of the osteoarthritis disease process and will need to be surmounted if treatment with exogenous GDF5 is to be advanced as a potential means to overcome the genetic deficit conferring osteoarthritis susceptibility at this gene.
The discovery of a novel variant near the NCOA3 (nuclear receptor coactivator 3) gene associated with hip OA and the regulation of GDF5 gene by four transcription factors via the OA susceptibility locus rs143383 are among important findings in OA genetics.
CpG methylation regulates allelic expression of GDF5 by modulating binding of SP1 and SP3 repressor proteins to the osteoarthritis susceptibility SNP rs143383.
In conclusion, we have identified four trans-acting factors that are binding to GDF5, three of which are modulating GDF5 expression via the OA susceptibility locus rs143383.
Since OA progression is clinically the most relevant phenotype, we investigate the association between asporin (ASPN), bone morphogenetic protein 5 (BMP5) and growth differentiation factor 5 (GDF5) polymorphisms and progression of hand OA.