FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis

Aims: Osteoclast energy metabolism is a promising target for treating diseases characterized by high osteoclast activity, such as osteoporosis. However, the regulatory factors involved in osteoclast bioenergetic processes are still in the early stages of being fully understood. This study reveals the effects of follicle-stimulating hormone (FSH) on osteoclast energy metabolism. Methods: The Lyz2-Cre-Flox model selectively deletes FSH receptor (FSHR) from osteoclast precursor cells to generate Fshrf/f; Lyz2-Cre (Fshrf/f; Cre) mice. Bone quality was assessed using micro-computed tomography, histomorphometric analysis, and dual-fluorescence labeling. The in vitro assays measured oxygen consumption rate, extracellular acidification rate, pyruvate content, and mitochondrial membrane potential to determine metabolic flux. RNA-seq, LC-MS, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays were used to elucidate the underlying mechanisms. Results: FSHR deficiency in osteoclasts protected bone from resorption under normal and ovariectomized conditions. FSHR-deficient osteoclasts have reduced nicotinamide adenine dinucleotide (NAD+) levels, impairing osteoclast activity and energy metabolism. Mechanistically, FSH influenced NAD+ levels via the CREB/MDH2 axis. Treatment with FSH monoclonal antibodies rescued bone loss in OVX mice and reduced bone marrow NAD+ levels. Conclusions: Targeting FSH may be a promising metabolic modulation strategy for treating osteoporosis and other diseases associated with high osteoclast activity.