{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:11:38Z","timestamp":1773900698606,"version":"3.50.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF18OC0055047"],"award-info":[{"award-number":["NNF18OC0055047"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["224155\/Z\/21\/Z"],"award-info":[{"award-number":["224155\/Z\/21\/Z"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC) at the University of Birmingham"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>G protein-coupled receptor 35 (GPR35) is an orphan receptor that is widely expressed in tissues, including human osteoblasts and osteoclasts. Expression of the GPR35 gene and protein is downregulated in osteoporosis patients and in mouse models of the disease. Gpr35-knockout mice have reduced bone mass, while GPR35 agonism rescues bone loss in rodent osteoporosis models, indicating that GPR35 has an important role in bone. Our previous studies demonstrated GPR35 is expressed in human osteoclasts, and we sought to determine the receptors function in these cells. We differentiated human peripheral blood mononuclear cells to mature osteoclasts and assessed effects of the GPR35 synthetic agonists, TCG1001 and Zaprinast, on osteoclast activity and differentiation. Both agonists stimulated significant reductions in osteoclast bone resorption and tartrate-resistant acid phosphatase (TRAP) activity, and downregulated expression of MMP9, a gene that regulates osteoclast bone resorption. These effects were prevented by pre-incubation of cells with a GPR35-specific antagonist. To understand GPR35 signaling pathways, we measured the phosphorylation of secondary messengers known to have important roles in osteoclast activity using AlphaLISA assays. Upon GPR35 stimulation, we observed reduced phosphorylation of c-Src, which stimulates actin ring formation necessary for bone resorption, and decreased phosphorylation of Akt, cyclic AMP (cAMP) response element-binding protein, and nuclear factor \u03baB that drive transcription of genes required for bone resorption. Additionally, we used chemical inhibitors and siRNA knockdown to show that GPR35 couples to Gi\/o and G12\/13 to stimulate these signaling pathways. Finally, we compared the ability of GPR35 agonists to suppress osteoclast activity to that of current osteoporosis drugs, denosumab and alendronic acid, and showed TRAP activity was similarly suppressed under all conditions. Our findings demonstrate that GPR35 has an important inhibitory role in human osteoclast activity and have defined the signaling pathways that drive these processes. GPR35 represents a promising novel target to reduce osteoclast activity that could be exploited for osteoporosis treatments.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf131","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T11:34:39Z","timestamp":1754393679000},"source":"Crossref","is-referenced-by-count":4,"title":["G protein-coupled receptor 35 stimulation reduces osteoclast activity in primary human bone cells"],"prefix":"10.1093","volume":"9","author":[{"given":"Maria L","family":"Price","sequence":"first","affiliation":[{"name":"Department of Metabolism and Systems Science and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham , Birmingham B15 2TT ,","place":["United Kingdom"]},{"name":"Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham , Birmingham B15 2TT ,","place":["United 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of Birmingham , B15 2TT ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aqfan","family":"Jamaluddin","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Systems Science and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham , Birmingham B15 2TT ,","place":["United Kingdom"]},{"name":"Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham , Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rowan S","family":"Hardy","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Systems Science and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham , Birmingham B15 2TT ,","place":["United Kingdom"]},{"name":"Department of Biomedical Sciences, University of Birmingham , Birmingham B15 2TT ,","place":["United 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