New chimeric peptide regulating insulin-like growth factor 1 regenerative effect for therapy in early stage osteoarthritis

Abstract

Purpose: Osteoarthritis (OA) is the most frequent chronic musculoskeletal disease and knee OA is becoming the 4th most important global cause of disability in women and 8th in men. Early OA is estimated to affect nowadays more than 8.5 million of persons worldwide, this figure being estimated to reach 13.5 million in 2023. The 1st phase of osteoarthritis is the loss of cartilage. Due to his avascularity and his low number of stem cells, cartilage has a low mitotic activity and, consequently, cartilage has low ability to self-repair. Insulin-like growth factors-1 (IGF-I) is one of the most important growth factor and it’s involved in the regulation of chondrocyte metabolic function, as both a proliferative and differentiative factor. IGF-I is able to increase cell migration and also has an important function in an endocrine/paracrine and autocrine stimulating of matrix synthesis (proteoglycan and collagen type II). A new innovative chimeric peptide was developed to act on the balance of synthesis of IGF-I. This peptide combines a short amino acid sequence derived from growth hormone (GH) and an analog of somatostatin (SST). This two sequences, having an opposite effect on IGF-I releasing, induce a balanced regulation of IGF-I synthesis and its receptor expression (IGF-IR). We wanted to explore in vitro, on human chondrocytes cells culture, the effect of our chimeric peptide on stimulation of IGF-IR production as well as chondrocytes proliferation and differentiation. In addition, we evaluated his activity in in vivo spontaneous knee OA model. Methods: Human normal chondrocyte cell line was cultivated in cell growth medium with or without peptide. Cells were collected after 2, 4 and 8 days of culture. The total IGF-IR concentration was quantified using ELISA kit. The chondrogenic effect was observed by microscopy after staining with alcian blue to visualise proteoglycans. Five months old Duncan-Hartley guinea pigs (early OA) received one peptide or sham intraarticular injection per week for three weeks. Seven animals per group were used. Guinea pigs were sacrificed at 10 month old and both knees were collected for histology according OARSI-HISTOgp recommendations. Results: This GH-SST peptide increased the production of IGF-IR in human chondrocytes. The alcian blue staining revealed an increasing of cell clusters indicating a stimulation of chondrogenesis. In vivo test confirm the effect of this GH-SST peptide. Five months after injection, the quantitative histologic evaluation of knee guinea pig revealed that the GH-SST peptide injected group had a cartilage thickness significantly superior to the control group. Moreover, semiquantitative histologic scoring evaluation revealed a decrease of osteophytes development. Conclusions: This GH-SST peptide, by acting on IGF-I axis, improved the stimulation of chondrocyte cell growth and may be involved in the synthesis and maintenance of cartilage tissue. Indeed, this GH-SST peptide showed a long term effect to slow down tissues degeneration in knee OA model and preserved a better cartilage thickness. These results suggest that the GH-SST peptide may be an effective treatment of early articular cartilage defects.