FDA-approved polypeptide PTH 1–34 impedes palmitic acid-mediated osteoblasts dysfunction by promoting its differentiation and thereby improving skeletal health

Abstract

Excessive consumption of saturated fatty acids creates a debilitating cellular environment that hinders the normal function and survival of osteoblasts, contributing to bone metabolic disorders such as osteoporosis. The FDA-approved polypeptide PTH 1–34 is a well-established therapy for post-menopausal osteoporosis, yet its protective effects in a palmitic acid (PA)-rich hyperlipidemic environment are not well understood. This study investigates the impact of PTH 1–34 on PA-induced cellular responses in osteoblasts. Experiments were conducted on mouse and human-derived osteoblasts as well as C57BL/6J male mice. PA was found to suppress osteoblast differentiation, increase apoptosis, and disrupt autophagy, and thereby impair cellular health. Conversely, PTH 1–34 enhanced cellular health by counteracting these effects. At the molecular level, PTH 1–34 exerted its bioactivity by modulating PTH signaling components such as cAMP and CREB. Impaired osteogenic differentiation was restored by modulating bone-anabolic genes. PTH 1–34 also improved mitochondrial health by preserving mitochondrial membrane potential and maintaining the Bax/Bcl2 ratio, thereby improving cellular viability. Additionally, PTH 1–34 regulated autophagic processes, as evidenced by balanced p62 and LC3 levels, further validated using the autophagy inhibitor Bafilomycin A1. In vivo studies in C57BL/6J male mice corroborated these findings. PTH 1–34 reversed the PA action by maintaining osteoblast number and function. This study establishes the protective role of PTH 1–34 in safeguarding osteoblasts from lipotoxicity caused by excessive PA accumulation, highlighting its potential repurposing for patients with lipid-induced skeletal dysfunctions. The new data underscores the therapeutic versatility of the FDA-approved polypeptide PTH 1–34 in managing lipid-related bone health issues.