How gene targeting could help to treat osteoporosis

A new study has uncovered a promising gene that could be targeted when devising new treatments for osteoporosis.

Osteoporosis is a skeletal condition that leads to the weakening of bones, making them porous, fragile and prone to breakage.

The ageing population is the most vulnerable to primary osteoporosis, given their frailty — and these individuals often require long-term therapy and support. Advances in health care and the corresponding rise in the ageing population have put a strain on available resources, highlighting the need for effective therapies against osteoporosis.

As part of the study, Professor Tadayoshi Hayata and Chisato Sampei, along with their colleagues at the Tokyo University of Science, conducted a series of experiments to identify druggable target genes downstream of parathyroid hormone (PTH) signalling in osteoblasts. They discovered that ‘Gprc5a’ — a novel inducible target gene of PTH — could be key to developing treatments for osteoporosis.

The role of the teriparatide drug

Induction of PTH signalling 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.

“Teriparatide is classified as a drug that promotes bone formation, but it also promotes bone resorption, which may limit bone formation. However, the full scope of its pharmacological action remains unknown,” said Hayata in the study, which was published in the Journal of Cellular Physiology.

PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialised cells responsible for bone resorption. Although bone remodelling 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 signalling in bone remodelling are not well understood.

What did the study involve?

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 overall findings of the study reveal that Gprc5a — a novel inducible target gene of PTH — negatively regulates osteoblast proliferation and differentiation, by partially suppressing bone morphogenetic protein signalling. Gprc5a can thus be pursued as a novel therapeutic target while devising treatments against osteoporosis. The study sheds light on the complex process of bone remodelling and explains the bone-promoting and bone-resorbing effects of PTH 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,” Hayata said.

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