New study reveals promising drug target for treating osteoporosis

Knee x-ray

Researchers have identified a novel target downstream of parathyroid hormone (PTH) signalling that suppresses bone formation in osteoporosis.

The PTH-derived peptide teriparatide has demonstrated strong bone promoting effects. However, it is also to known to exert bone-resorbing effects.

A new study uncovers a novel PTH-inducible target gene – Gprc5a which suppresses the proliferation and differentiation of ‘osteoblasts’ or bone-forming cells, and may serve as a therapeutic target in the treatment of osteoporosis.

Induction of parathyroid hormone (PTH) signalling using the PTH-derived peptide – teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis.

However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialised cells responsible for bone resorption.

The role of gene Gprc5a

Professor Tadayoshi Hayata and Chisato Sampei, from Tokyo University of Science, along with their colleagues, conducted a series of experiments to identify druggable target genes downstream of PTH signalling 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 treated animals using 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.

PTH induction has been known to activate the cyclic adenosine monophosphate (cAMP) and protein kinase C (PKC) signalling pathways. Interestingly, the team found that in addition to PTH induction, activation of cAMP and PKC also resulted in overexpression of Gprc5a, albeit to a lesser extent, underscoring the potential involvement of other molecular pathways.

Notably, upregulation of Gprc5a was suppressed upon inhibition of transcription, but remained unaffected upon suppressing protein synthesis, suggesting that Gprc5a could be transcribed early on in response to PTH signalling and serves as a direct target gene.

Their findings reveal that Gprc5a, a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation, by partially suppressing BMP signalling.

“Our study shows Gprc5a may function as a negative feedback factor for the bone formation promoting effect of teriparatide. Suppressing Gprc5a function may, therefore, increase the effectiveness of teriparatide in non-responding patients. In the future, we hope that our research will lead to improved quality of life and healthy longevity for people suffering from osteoporosis,” said Professor Hayata.

Diana Spencer, Senior Digital Content Editor, DDW

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