DUSP26: Unveiling a critical molecular mediator and therapeutic target in developmental dysplasia of the hip‑associated secondary osteoarthritis

Secondary osteoarthritis, a degenerative joint disease, is often precipitated by well-characterized etiological factors, with developmental dysplasia of the hip (DDH) emerging as a leading contributor.Despite its clinical importance, the intricate molecular and cellular cascades triggered by the biomechanical perturbations associated with DDH remain poorly understood.In the present study, a swaddling-induced rat model of DDH was successfully developed, which recapitulated key pathological features including acetabular labral tears and cartilage degeneration.Through comprehensive mRNA-sequencing analysis of acetabular cartilage samples from rats with DDH, a notable upregulation of dual-specificity phosphatase 26 (DUSP26) was identified, a protein with previously unreported roles in joint homeostasis.Subsequently, in an in vitro inflammatory microenvironment induced by interleukin (IL)-1β, adenovirus-mediated overexpression of DUSP26 demonstrated marked chondroprotective effects.Specifically, this intervention led to a significant increase in the expression of type II collagen, a hallmark of healthy chondrocytes, while concurrently reducing the levels of catabolic markers such as type I collagen, TNF-α and IL-6.Reciprocally, adenovirus-delivered short hairpin RNA-mediated DUSP26 silencing exacerbated cartilage degradation, validating its protective function.Employing mass spectrometry-based proteomics combined with genetic and pharmacological approaches, the underlying mechanism was elucidated: DUSP26 overexpression exerted its chondroprotective effects by dephosphorylating and inactivating histone deacetylase (HDAC)1, HDAC2 and HDAC8, thereby maintaining chondrocyte integrity.Collectively, the findings of the present study underscore DUSP26 as a promising therapeutic target for DDH-associated osteoarthritis, offering novel mechanistic insights and laying the groundwork for the development of targeted interventions to mitigate secondary joint degeneration.