more susceptible to fractures and decreasing the overall quality of life for the elderly population. The peptide teriparatide, derived from the parathyroid hormone (PTH), has shown to have strong positive effects on bone promotion. However, it is also known to have negative effects on bone resorption. A recent study has discovered a new gene, Gprc5a, that is induced by PTH and has the ability to suppress the proliferation and differentiation of osteoblasts, or bone-forming cells. This finding suggests that Gprc5a may be a potential target for therapeutic treatment of osteoporosis.
Osteoporosis is a skeletal condition that leads to the weakening of bones, making them more susceptible to fractures and decreasing the overall quality of life for the elderly population. The peptide teriparatide, derived from the parathyroid hormone (PTH), has shown to have strong positive effects on bone promotion. However, it is also known to have negative effects on bone resorption. A recent study has discovered a new gene, Gprc5a, that is induced by PTH and has the ability to suppress the proliferation and differentiation of osteoblasts, or bone-forming cells. This finding suggests that Gprc5a may be a potential target for therapeutic treatment of osteoporosis.Porous, fragile, and prone to breakage. Osteoporosis causes a whopping 8.9 million fractures each year, with one fracture happening every three seconds! The elderly population is particularly at risk for primary osteoporosis due to their frailty, often requiring long-term therapy and support. The increasing number of elderly individuals and advances in healthcare have placed a strain on available resources, highlighting the need for effective osteoporosis therapies.
Using the PTH-derived peptide teriparatide to induce parathyroid hormone (PTH) signaling has shown strong bone-promoting effects.Effects in patients with osteoporosis are a result of osteogenesis, which is the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts.
However, PTH induction is also linked to the differentiation of macrophages into osteoclasts, which are specialized cells responsible for bone resorption.
While bone remodeling by osteoblasts and osteoclasts is essential for maintaining skeletal health, PTH-induced osteoclast differentiation can reduce treatment efficacy in patients with osteoporosis.
The precise molecular mechanisms underlying the dual action of PTH signaling in bone remodeling are still unclear.The field of remodeling is not well understood. Professor Tadayoshi Hayata and Ms. Chisato Sampei, along with their colleagues from Tokyo University of Science, conducted a series of experiments to identify druggable target genes downstream of PTH signaling in osteoblasts in order to bridge this gap. Their study was published on 20 May, 2024, in the Journal of Cellular Physiology. Prof. Hayata explained that in Japan, it is estimated that 12.8 million people, or one in ten people, suffer from osteoporosis, which can significantly deteriorate their quality of life. Teriparatide is classified as a drug.The article highlights the dual effects of teriparatide, a drug that both stimulates bone formation and bone resorption, which could potentially limit its effectiveness in promoting bone growth. The researchers conducted experiments on mouse osteoblast cells and mice treated with teriparatide to understand the gene expression changes caused by the drug. Using advanced RNA-sequencing analysis, they identified a new gene called ‘Gprc5a’ that was activated by teriparatide, which encodes an orphan G protein-coupled receptor and has previously been considered as a potential target for therapeutic purposes.The exact role of PTH in osteoblast differentiation had not yet been fully comprehended. PTH induction is known to activate cAMP and PKC signaling pathways. Additionally, the study revealed that activation of cAMP and PKC led to increased expression of Gprc5a, although to a lesser degree, indicating potential involvement of other molecular pathways. Significantly, the upregulation of Gprc5a was inhibited when transcription was suppressed, but remained unaffected when protein synthesis was suppressed, suggesting that Gprc5a may be transcribed early in the process.Response to PTH signaling and acts as a direct target gene. Additionally, the scientists studied the impact of decreasing Gprc5a on osteoblast proliferation and differentiation. Interestingly, PTH stimulation alone did not influence cell proliferation, but knocking down Gprc5a led to an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These results indicate that Gprc5a inhibits osteoblast proliferation and differentiation. Delving into the molecular mechanisms of Gprc5a’s effects on PTH-induced osteogenesis, the researchers discovered Activin receptor-like kinase.The bone morphogenetic protein (BMP) signaling pathway receptor, ALK3, was found to interact with Gprc5a. The researchers found that overexpression of Gprc5a led to the suppression of BMP signaling through receptors, including ALK3.
these findings demonstrate that Gprc5a, a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation by partially suppressing BMP signaling. Gprc5a could be considered a potential therapeutic target in the development of treatments for osteoporosis. This study provides insight into the complex process of bone remodeling and explains the bone-promoting and bone-protective effects of Gprc5a.The study demonstrates that Gprc5a could act as a negative feedback factor for the bone formation promoting effect of teriparatide. By inhibiting Gprc5a function, the effectiveness of teriparatide in non-responding patients may be enhanced. The researchers are optimistic that this research will ultimately lead to better quality of life and healthy longevity for individuals with osteoporosis. These findings also hold promise for the development of effective therapies to improve the lives of those affected by osteoporosis.
