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

Abstract

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 aninflammatory 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.