{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:12:43Z","timestamp":1781104363742,"version":"3.54.1"},"reference-count":76,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:p>\n                    Melatonin is a promising drug for improving bone mass in postmenopausal women. This study investigated the mechanism behind the regulation of melatonin on osteoblast differentiation. Mouse embryonic osteoblast precursor MC3T3-E1 cells were treated with melatonin or transfected with cathepsin D (CTSD) vectors. A cellular model was established by H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    treatment. Alkaline phosphatase (ALP) staining and Alizarin Red S staining were performed. An osteoporosis mouse model was established by ovariectomy (OVX) and treated with melatonin or transfected with a CTSD knockdown vector. Bone biomechanical testing was performed to assess bone strength. Histological bone damage was assessed, osteoclast differentiation was visualized using tartrate-resistant acid phosphatase staining, osteocalcin (OCN) and type I collagen \u03b11 chain (COL1A1) expression was visualized using immunohistochemistry, and serum bone turnover markers procollagen type I N-propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX-1) levels were measured using enzyme-linked immunosorbent assay. Receptor activator of NF-\u03baB ligand (RANKL), osteoprotegerin (OPG), Wnt3a, and \u03b2-catenin protein levels were determined using western blotting. Melatonin treatment or CTSD overexpression promoted ALP activity and mineralization in MC3T3-E1 cells. Melatonin upregulated CTSD expression. Melatonin treatment enhanced bone strength, inhibited osteoclast differentiation, increased OCN and COL1A1 expression, elevated PINP levels, and reduced CTX-1 in OVX mice. Moreover, melatonin suppressed RANKL expression and promoted OPG, Wnt3a, and \u03b2-catenin expression. CTSD knockdown abolished the regulatory effects of melatonin on MC3T3-E1 cells and OVX mice. In conclusion, melatonin increases CTSD expression to promote osteoblast differentiation and regulate the RANKL\/OPG\/Wnt signaling pathway, thereby slowing down the progression of osteoporosis.\n                  <\/jats:p>","DOI":"10.1530\/jme-25-0220","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T10:43:18Z","timestamp":1776940998000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":0,"title":["The molecular mechanism of melatonin in regulating osteoporosis based on the RANKL\/OPG signaling axis"],"prefix":"10.1530","volume":"76","author":[{"given":"Tai","family":"Guo","sequence":"first","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqing","family":"Jia","sequence":"additional","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Hao","sequence":"additional","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Hu","sequence":"additional","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0625-2354","authenticated-orcid":true,"given":"Lin","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Best Pract Res Clin Endocrinol Metab","article-title":"Menopausal hormone therapy for the management of osteoporosis","volume":"35","author":"Gosset A","year":"2021","unstructured":"Gosset A\n, \nPouilles JM\n & \nTremollieres F\n\n. Menopausal hormone therapy for the management of osteoporosis. Best Pract Res Clin Endocrinol Metab 2021 35 101551. (https:\/\/doi.org\/10.1016\/j.beem.2021.101551)"},{"key":"bib2","series-title":"Endocrinol Metab Clin North Am","first-page":"497","article-title":"Postmenopausal osteoporosis: a review of latest guidelines","volume":"53","author":"Subarajan P","year":"2024","unstructured":"Subarajan P\n, \nArceo-Mendoza RM\n & \nCamacho PM\n\n. Postmenopausal osteoporosis: a review of latest guidelines. Endocrinol Metab Clin North Am 2024 53 497\u2013512. (https:\/\/doi.org\/10.1016\/j.ecl.2024.08.008)"},{"key":"bib3","series-title":"N Engl J Med","first-page":"1979","article-title":"Postmenopausal osteoporosis","volume":"389","author":"Walker MD","year":"2023","unstructured":"Walker MD\n & \nShane E\n\n. Postmenopausal osteoporosis. N Engl J Med 2023 389 1979\u20131991. 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(https:\/\/doi.org\/10.1016\/j.beem.2021.101551)"},{"key":"bib2","series-title":"Endocrinol Metab Clin North Am","first-page":"497","article-title":"Postmenopausal osteoporosis: a review of latest guidelines","volume":"53","author":"Subarajan P","year":"2024","unstructured":"Subarajan P\n, \nArceo-Mendoza RM\n & \nCamacho PM\n\n. Postmenopausal osteoporosis: a review of latest guidelines. Endocrinol Metab Clin North Am 2024 53 497\u2013512. (https:\/\/doi.org\/10.1016\/j.ecl.2024.08.008)"},{"key":"bib3","series-title":"N Engl J Med","first-page":"1979","article-title":"Postmenopausal osteoporosis","volume":"389","author":"Walker MD","year":"2023","unstructured":"Walker MD\n & \nShane E\n\n. Postmenopausal osteoporosis. N Engl J Med 2023 389 1979\u20131991. (https:\/\/doi.org\/10.1056\/NEJMcp2307353)"},{"key":"bib4","series-title":"Int J Mol Sci","first-page":"15772","article-title":"Molecular and cellular mechanisms of osteoporosis","volume":"24","author":"Zhivodernikov IV","year":"2023","unstructured":"Zhivodernikov IV\n, \nKirichenko TV\n, \nMarkina YV\n, et al.\n Molecular and cellular mechanisms of osteoporosis. Int J Mol Sci 2023 24 15772. (https:\/\/doi.org\/10.3390\/ijms242115772)"},{"key":"bib5","series-title":"Nutrients","first-page":"3480","article-title":"Circadian rhythm dysregulation and restoration: the role of melatonin","volume":"13","author":"Vasey C","year":"2021","unstructured":"Vasey C\n, \nMcBride J\n & \nPenta K\n\n. Circadian rhythm dysregulation and restoration: the role of melatonin. Nutrients 2021 13 3480. 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