Novel insights into the complex architecture of osteoporosis molecular genetics

Osteoporosis is a prevalent osteodegenerative disease and silent killer linked to a decrease in bone mass and decline of bone microarchitecture, due to impaired bone matrix mineralization, raising the risk of fracture. Nevertheless, the process of bone matrix mineralization is still an unsolved mystery. Osteoporosis is a polygenic disorder associated with genetic and environmental risk factors; however, the majority of genes associated with osteoporosis remain largely unknown. Several signaling pathways regulate bone mass; therefore, dysregulation of a single signaling pathway leads to metabolic bone disease owing to high or low bone mass. Parathyroid hormone, core-binding factor α-1 (Cbfa1), Wnt/β-catenin, the receptor activator of the nuclear factor kappa-B (NF-κB) ligand (RANKL), myostatin, and osteogenic exercise signaling pathways play pivotal roles in the regulation of bone mass. The myostatin signaling pathway increases bone resorption by activating the RANKL signaling pathway, whereas osteogenic exercise inhibits myostatin and sclerostin while inducing irisin that consequentially activates the Cbfa1 and Wnt/β-catenin bone formation pathways. The aims of this review are to summarize what is known about osteoporosis-related signaling pathways; define the role of these pathways in osteoporosis drug discovery; focus light on the link between bone, muscle, pancreas, and adipose integrative physiology and osteoporosis; and underline the emerging role of osteogenic exercise in the prevention of, and care for, osteoporosis, obesity, and diabetes.