giovedì, Luglio 18, 2024

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Osteoporosis is a skeletal condition that leads to the weakening of bones, making them porous, fragile, and prone to breakage. A whopping 8.9 million fractures are caused by osteoporosis annually. The aging population is the most vulnerable to primary osteoporosis, given, their frailty, and often, requires long-term therapy and support. Advances in healthcare and the corresponding rise in the aging population have put a strain on available resources, underscoring the need for effective therapies against osteoporosis. Induction of parathyroid hormone (PTH) signaling using the PTH-derived drug 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 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 still unclear. To bridge this gap, scientists from Tokyo University of Science 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 the treated animals.

Among several upregulated genes, they identified a novel PTH-induced gene, ‘GPCR5a‘, 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. PTH induction has been known to activate both the cyclic adenosine monophosphate (cAMP) and protein kinase C (PKC) signaling 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 extentNotably, 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 signaling and serves as a direct target gene.

Furthermore, 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. Gprc5a expression was induced additively by co-treatment with PTH and active vitamin D3 (calcitriol) or retinoic acid. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation. Diving deeper into the molecular mechanisms, the researchers identified ALK3 receptor, a bone morphogenetic protein (BMP) signaling pathway family member, as an interacting partner of Gprc5a. In line with their speculation, overexpression of Gprc5a indeed, led to suppression of BMP signaling via receptors including ALK3.

Overall, these findings reveal that Gprc5a 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. It is remarkable that natural ligands of Gprc5a have been identified among microbiota catabolites, in particolar aromatic derivatives like tryptamine. Once activated, the receptor recruits beta-arrestin and crosstalks with beta1-integrin signaling, as demonstrated in lung cancer cells. From one hand, this would give credit to the recent connection between gut microbiota dysbiosis and osteopenia risk; on the other side, it would partially explain the mechanisms of this receptor in controlling bone cell maturation and even motility or homing.

Gprc5a therefore may work as a negative feedback factor for the bone formation promoting effect of teriparatide. Suppressing Gprc5a function may, thus, increase the effectiveness of teriparatide in non-responding patients.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Sampei C, Kato K, Arasaki Y et al. J Cell Physiol. 2024 May 20.

Zhao X, Stein KR et al. Nat Chem Biol. 2023; 19(10):1205-14.

Balani DH, Ono N et al. J Clin Invest. 2017; 127(9):3327–338.

Cheng Y, Lotan R. J Biol Chem. 1998; 273(52), 35008–35015.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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