Chimeric peptide combining both growth hormone and somatostatin sequences (REG-O3) improves function and prevents cartilage degradation in rat model of osteoarthritis

Abstract

Purpose: REG-O3 is an innovative chimeric peptide combining a short amino acid sequence derived from growth hormone (GH) and an analog of somatostatin (SST), both well-known molecules for their involvement in skeletal development and maintenance via their action on IGF-1-dependent pathways. This peptide was therefore thought to show disease modifying osteoarthritis drug (DMOAD) potential and protect articular structure from osteoarthritis (OA). The aim of this study was thus to investigate the protective effect of this peptide directly injected into the knee joint on pain and function, and on joint tissues structure. Methods: Mature male Lewis rats (n=12/group) were used for this study. OA was induced in the right knee by the surgical transection of the anterior cruciate ligament (ACLT) combined with the partial medial meniscectomy (pMMx). Treatments were administered intra-articularly (50μL) into the right operated knee from 14 days after surgery through 3 consecutive injections one week apart. The test item (REG-O3) was solubilized in a liposomal solution and was injected into the right operated knee at 10, 50 and 100μM final concentrations. It was compared to placebo (liposomal solution), and positive control items such as dexamethasone (0.5 mg/kg) and hyaluronic acid (HA, 1 mg/kg). The study endpoints were the pain and function measured throughout the entire study once a week and the structure of the knee joint evaluated 8 weeks after surgery using OARSI score. Results: ACLT+pMMx surgery induced a significant decrease of right operated paw weight bearing in all groups. Dexamethasone and HA treatments partially but significantly increased right paw weight bearing compared to placebo. REG-O3 displayed a similar effect to dexamethasone and higher effects than HA on weight bearing recovery after surgery. When looking at cartilage histology, REG-O3 (50μM) was the only treatment able to significantly improve cartilage OARSI global score and to significantly reduce total cartilage degeneration width, cartilage matrix loss width and cartilage degeneration. Conclusions: REG-O3 not only exhibited an interesting profile on function and pain in ACLT+pMMx model of OA in rat but was also able to significantly preserve cartilage from degeneration. REG-O3 might be a drug candidate for the treatment of OA.