1803-P: Protective Effects of HM17321, a Novel UCN2 Analog, on Obesity-Associated Musculoskeletal Diseases in Mouse Models

Introduction and Objective: Obesity increases the risk of musculoskeletal diseases including osteoarthritis (OA) and osteoporosis (OP). Weight-loss medications are shown to improve musculoskeletal outcomes by reducing joint load, but lean mass preservation is also crucial for stabilizing joints, protecting bone density and mitigating frailty and functional decline. HM17321 is a novel CRFR2 selective UCN2 analog and has been demonstrated to improve weight loss quality by enhancing both muscle hypertrophy and lipolysis in obese mice. In this study, we aim to evaluate therapeutic potential of HM17321 on obesity-related OA and OP. Methods: We utilized two distinct in vivo models: the surgical destabilization of the medial meniscus (DMM)-induced OA and ovariectomy (OVX)-induced OP in HFD-fed mice. HM17321 (100 nmol/kg) or semaglutide (20 nmol/kg) were administered in HFD/DMM mice for 6 weeks and then motor function and histology of cartilage were assessed. In a second study, HFD/OVX mice were treated with HM17321 or semaglutide for 8 weeks and then serum markers and muscle function were evaluated. Results: HM17321 consistently led to a significant fat reduction and increase in lean and skeletal muscle mass in both HFD/DMM and HFD/OVX mice. Notably, HM17321 significantly improved weight bearing (92.1% vs. 80.5%, vehicle; 99.6%, Sham vehicle) and locomotor activity in HFD/DMM mice. OARSI score for joint cartilage was lowered by HM17321 (7.3 vs. 9.6, vehicle; 0.6, Sham vehicle). In HFD/OVX mice, HM17321 significantly decreased serum CTX-1/P1NP ratio (0.11 vs. 0.20, vehicle; 0.14, Sham vehicle) suggesting a shift toward a more balanced bone remodeling. Moreover, functional improvement of muscle was observed in HM17321-treated HFD/OVX mice, compared to semaglutide. Conclusion: HM17321 resulted in a significant fat reduction simultaneously increasing lean mass in obesity-associated OA and OP mice. These favorable changes in body composition, beyond simple weight loss, may contribute to more effectively improve obesity-associated OA and OP. Disclosure H. Kwon: Employee; Current; Hanmi Pharm. Co., Ltd. B. Ye: Employee; Current; Hanmi Pharm. Co., Ltd. W. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. S. Lee: None. J. Kim: None. S. Bae: None. S. Lee: Employee; Current; Hanmi Pharm. Co., Ltd. I. Choi: None.