SAT-807 Kisspeptin Prevents Bone Loss Caused by the Lack of Estrogen in Ovariectomized Rodents

Abstract Disclosure: M.D. Santos: None. R. Araujo-Lopes: None. I.B. Alves: None. A.C. Campideli-Santana: None. P.C. Henriques: None. D.M. dos Santos: None. L.P. Nogueira: None. G.J. Dias: None. D.R. Grattan: None. S. Macari: None. R.E. Szawka: None. Kisspeptin (Kp) may exert direct action on bone. We tested the effect of Kp10 in preventing or reversing bone loss caused by ovariectomy in female rats and mice and determined the direct action of Kp10 on osteoblasts (OBL) and osteoclasts (OCL). Female Wistar rats and C57BL/6 mice were ovariectomized (OVX) or sham-operated. To characterize the temporal profile of bone loss, Sham and OVX rats were investigated at 1, 2, and 6 months (m) after ovariectomy. To evaluate the effects of Kp10, OVX and Sham rats were treated with s.c. Kp10 (1 nmol/day), saline (Veh), or E2. OVX mice received Kp10 at 0.5 or 1 nmol/day. The treatment duration was 30 days, starting on day 1 (prevention protocol, in rats and mice) or 30 (reversal protocol, in rats) after ovariectomy. Hormonal analyses were performed by ELISA, and the femur was analyzed by micro-CT, histology, and qPCR. Primary cultures of mouse OBL and OCL received 10-8, 10-7, or 10-6 M Kp10. In trabecular bone, ovariectomy decreased bone mineral density (BMD), bone volume ratio (BV/TV), and trabecular number (Tb.N), and increased trabecular separation (Tb.Sp) in all time points evaluated. Sham rats had reduced BMD and Tb.N at 6m. Ovariectomy gradually increased the quantity of bone marrow cells and adipocytes. In the cortical bone, ovariectomy increased the periosteal and endocortical perimeters and decreased the cortical/total area fraction after 1m and 2m. OVX rats exhibited increased body weight and luteinizing hormone levels and decreased uterine weight, effects restored by E2 but not Kp10. Ovariectomy also reduced E2 and testosterone and increased RANKL plasma levels. Kp10 treatment starting 1 day after ovariectomy was as effective as E2 in preventing the reductions in BV, BV/TV, and Tb.N and the increase in Tb.Sp, whereas only E2 prevented the decrease in BMD. When treatment started 30 days after ovariectomy, neither Kp10 nor E2 recovered bone loss. In OVX mice, 1 nmol Kp10 prevented the rise in plasma RANKL/OPG ratio and the reduction in BV, BV/TV, Tb.N, and Tb.Th. Kp10 also prevented the increases in Tnf-α and Il-6 and the decrease in Alp expression in the femur of OVX mice. In cell culture, all concentrations of Kp10 increased the deposition of OBL mineral nodules but did not affect OCL differentiation. In conclusion, Kp10 prevents bone loss caused by E2 withdrawal, enhancing OBL activity and mineralized matrix deposition while suppressing bone pro-inflammatory interleukins associated with osteoclastogenesis. Presentation: Saturday, July 12, 2025