Acute Effects of Kisspeptin Administration on Bone Metabolism in Healthy Men

Abstract

Context Osteoporosis results from disturbances in bone formation and resorption. Recent non-human data suggests that the reproductive hormone, kisspeptin, directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. Objective To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. Design In vitro study: Mono- and co-cultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, two-way crossover clinical study in twenty-six men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. Participants In vitro study: Twelve male blood donors and eight patients undergoing hip replacement surgery. Clinical Study: Twenty-six healthy eugonadal men (age 26.8±5.8 years). Intervention Kisspeptin (versus placebo). Main Outcome Measures Changes in bone parameters and turnover markers. Results Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P=0.0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P<0.0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P=0.021) and 24.3% maximal increase in carboxylated osteocalcin levels (P=0.014). Conclusions Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex-steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis.

Invited review: Translating kisspeptin and neurokinin B biology into new therapies for reproductive health

“…The neuropeptide kisspeptin has fundamental importance in mammalian reproduction, with a plethora of experimental animal models demonstrating its significance as the master regulator of GnRH and gonadotropin release. Moreover, outside of the classical reproductive axis, kisspeptin has increasingly established roles, including in reproductive behaviour, 109 metabolism, 110 bone biology 111,112 and cognition, 113 with imminent studies undoubtedly pending to dissect these functions in more detail (particularly in humans). The exciting reproductive observations in animal models has triggered significant interest in targeting the kisspeptin‐pathway to treat human reproductive disorders.…”

Bones and Hormones: Interaction between Hormones of the Hypothalamus, Pituitary, Adipose Tissue and Bone

“…Comninos et al [ 21 ] studied the effects of kisspeptin on human bone metabolism in vitro and in vivo. In vivo, they demonstrated, for the first time in humans, the promoting effects of kisspeptin on the osteogenic differentiation of osteoblast progenitors, and, in vitro, the inhibition of bone resorption.…”

Current Perspectives on Kisspeptins Role in Behaviour

“…Regarding humans, KISS1 mRNA expression is principally found in the placenta and testis, as well as moderate expression levels in the liver, pancreas, small intestine ( 9 , 11 ). Moreover, notable KISS1R mRNA expression is present in the placenta and pancreas, with lower expression levels in organs such as adipose tissue, kidney, liver, small intestine, spleen, stomach, testis and bone ( 9 – 11 , 39 ).…”