Osteoporosis is a common skeletal condition that weakens bones, making them more prone to fractures. The aging population is especially vulnerable to this condition, which causes a staggering 8.9 million fractures annually. Induction of parathyroid hormone (PTH) has been shown to promote bone formation in patients with osteoporosis, but it can also contribute to bone resorption by activating osteoclasts. The exact mechanisms underlying this dual action of PTH signaling in bone remodeling are not fully understood, highlighting the need for more effective therapies against osteoporosis.
To address this gap in knowledge, Professor Tadayoshi Hayata and Ms. Chisato Sampei, along with their colleagues at Tokyo University of Science, conducted a series of experiments to identify druggable target genes downstream of PTH signaling in osteoblasts. Through RNA-sequencing analysis of gene expression changes induced by PTH, they identified a novel gene called Gprc5a, which encodes a G protein-coupled receptor. The researchers found that Gprc5a negatively regulates osteoblast proliferation and differentiation, offering a potential target for novel therapies against osteoporosis.
In addition to PTH induction, activation of cAMP and PKC signaling pathways also resulted in the overexpression of Gprc5a, suggesting potential involvement of other molecular pathways. Suppression of Gprc5a led to an increase in osteoblast proliferation and differentiation, indicating its role in regulating bone formation. The researchers also found that Gprc5a interacts with Activin receptor-like kinase 3 (ALK3), a receptor in the bone morphogenetic protein (BMP) signaling pathway, and suppresses BMP signaling, further elucidating the molecular mechanisms underlying the effects of Gprc5a in PTH-induced osteogenesis.
Overall, the study sheds light on the complex process of bone remodeling and provides insights into the bone-promoting and bone-resorbing effects of PTH signaling. By identifying Gprc5a as a novel inducible target gene of PTH that negatively regulates osteoblast proliferation and differentiation, the researchers hope these findings will lead to the development of more effective treatments for osteoporosis. Suppressing Gprc5a function may increase the effectiveness of teriparatide in non-responding patients, ultimately improving the quality of life and longevity for those suffering from osteoporosis.