GPRC5A Inhibition as a Strategy to Enhance Bone Formation in Osteoporosis
Osteoporosis, the progressive age-related loss of bone mineral density, occurs due to an imbalance between the activities of osteoblast cells that build bone and osteoclast cells that break down bone. Both cell populations are constantly active, and thus balance must be maintained. Regulation of this balance is complicated, unfortunately, and the downstream effects of existing bone-promoting therapies are not fully understood. Researchers here investigate the mechanisms of a parathyroid hormone based treatment for osteoporosis, and find that GPRC5A expression suppresses the activity of osteoblasts. Thus inhibition of GPRC5A is a potential therapeutic target for future therapies aimed at enhancing bone deposition.
Induction of parathyroid hormone (PTH) signaling using the PTH-derived peptide - teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis. These effects are mediated by osteogenesis, the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts. However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialized cells responsible for bone resorption. Although, bone remodeling by osteoblasts and osteoclasts is crucial for maintaining skeletal health, PTH-induced osteoclast differentiation can decrease treatment efficacy in patients with osteoporosis. However, precise molecular mechanisms underlying the dual action of PTH signaling in bone remodeling are not well understood.
Researchers conducted a series of experiments to identify druggable target genes downstream of PTH signaling in osteoblasts. The researchers treated cultured mouse osteoblast cells and mice with teriparatide. They then assessed gene expression changes induced by PTH in both the cultured cells and bone cells isolated from the femurs of the treated animals, using advanced RNA-sequencing analysis. Among several upregulated genes, they identified a novel PTH-induced gene - 'Gprc5a', encoding an orphan G protein-coupled receptor, which has been previously explored as a therapeutic target. However, its precise role in osteoblast differentiation had not been fully understood.
The researchers examined the effect of Gprc5a downregulation on osteoblast proliferation and differentiation. Notably, while PTH induction alone did not affect cell proliferation, Gprc5a knockdown resulted in an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation. Diving deeper into the molecular mechanisms underlying the effects of Gprc5a, in PTH-induced osteogenesis, the researchers identified Activin receptor-like kinase 3 (ALK3), a bone morphogenetic protein (BMP) signaling pathway receptor, as an interacting partner of Gprc5a. Overexpression of Gprc5a led to suppression of BMP signaling.
Overall, these findings reveal that Gprc5a, a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation by partially suppressing BMP signaling. Gprc5a can thus, be pursued as a novel therapeutic target while devising treatments against osteoporosis.
Link: https://www.tus.ac.jp/en/mediarelations/archive/20240618_2891.html