Intra-articular silencing of periostin via nanoparticle-based siRNA ameliorates post-traumatic osteoarthritis in mice.

Objective Recent evidence delineates an emerging role of Periostin (Postn) in osteoarthritis (OA) as its expression subsequent to knee injury is detrimental to the articular cartilage. We hypothesize that intra-articular knockdown of Postn in a murine model of post-traumatic OA would ameliorate OA. Methods Post-traumatic OA was induced in 10-week-old male C57BL/6J mice (n=24) by destabilization of the medial meniscus (DMM) and analyzed 8-week post-surgery. Intra-articular Postn was inhibited by siRNA using a novel peptide-nucleotide polyplex. Cartilage degeneration (OARSI score) and synovitis were assessed histologically. Bone changes were measured by μCT. The effect and mechanism of Postn silencing were investigated in human chondrocytes treated with IL-1β with or without IKK2 inhibitor, SC-514. Results Peptide-siRNA nanoplatform significantly abolished Postn expression. OARSI score was significantly less in mice receiving Postn siRNA (10.94±0.66) compared to both untreated (22.38±1.30,P=0.002) and scrambled siRNA (22.69±0.87,P=0.002) treatment. No differences were observed in synovitis. Subchondral bone sclerosis, BV/TV, vBMD, and heterotopic ossification were significantly low in Postn siRNA treatment. Immunostaining of cartilage revealed that Postn knockdown reduced the DMM-induced MMP-13 intensity, phosphorylation of p65, and immunoreactivity of aggrecan neoepitope, DIPEN. Postn knockdown also suppressed IL-1β-induced MMP-13 and ADAMTS-4 in chondrocytes. Mechanistically, Postn-induced MMP-13 was abrogated by SC-514 demonstrating a link between Postn and NF-κB. Conclusion Intra-articular delivery of Postn siRNA nanocomplex represents a promising clinical approach to mitigate the severity of joint degeneration and provides an unequivocal scientific rationale for longitudinal studies. Employing a cartilage-specific gene knockout strategy will further illuminate the functional role of Postn in OA.