Antagonizing microRNA ‐19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice

Taipaleenmäki, Hanna; Saito, Hiroaki; Schröder, Saskia; Maeda, Miki; Mettler, Ramona; Ring, Matthias; Rollmann, Ewa; Gasser, Andreas; Haasper, Carl; Gehrke, Thorsten; Weiss, Alexander; Grimm, Steffen K; Hesse, Eric (2022): Antagonizing microRNA ‐19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice. EMBO Molecular Medicine, 14 (11). ISSN 1757-4676

Abstract

Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl-Ab). Here, we show that PTH and Scl-Ab reduce the expression of microRNA-19a and microRNA-19b (miR-19a/b) in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR-19a/b expression is elevated, suggesting an inhibitory function in bone remodeling. Indeed, antagonizing miR-19a/b in vivo increased bone mass without overt cytotoxic effects. We identified TG-interacting factor 1 (Tgif1) as the target of miR-19a/b in osteoblasts and essential for the increase in bone mass following miR-19a/b inhibition. Furthermore, antagonizing miR-19a/b augments the gain in bone mass by PTH and restores bone loss in mouse models of osteoporosis in a dual mode of action by supporting bone formation and decreasing receptor activator of NF-κB ligand (RANKL)-dependent bone resorption. Thus, this study identifies novel mechanisms regulating bone remodeling, which opens opportunities for new therapeutic concepts to treat bone fragility.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > MUM - Musculoskeletal University Center Munich
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 401298360
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892