Relaxin and insulin-like peptide 3 in the musculoskeletal system: from bench to bedside

Skeletal muscles and bones form a joined functional unit sharing a complex mechanical, biochemical and hormonal crosstalk. A number of factors, including sex hormones, physiologically regulate the musculoskeletal system. Striking gender differences in muscle and bone mass, and function are mainly caused by distinct actions exerted by oestrogens and androgens. However, relaxin and relaxin-related peptides, such as insulin-like peptide 3 (INSL3), might contribute to these sex-associated differences in physiological and pathological conditions (such as osteoporosis and sarcopenia). Relaxin is a 'pregnancy' hormone, but it is also produced from the prostate gland, and has recently attracted attention as a potential drug for cardiovascular disorders and fibrosis. In contrast, INSL3 is a male-specific hormone produced by the Leydig cells of the testis with a fundamental role in testicular descent during fetal life. Recent evidence suggests that both hormones have interesting roles in the musculoskeletal system. Relaxin and INSL3, by finely tuning bone formation and resorption, are involved in bone remodelling processes, and relaxin contributes to the healing of injured ligaments and promotes skeletal muscle regeneration. Here, we review the most recent findings on the effects of relaxin and INSL3 on skeletal muscle and the cell components of bone. In the light of the experimental evidence available and animal models, their clinical implications are also discussed.