{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:03:10Z","timestamp":1787166190261,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Small and Medium-sized Enterprises (SMEs) and Startups","award":["S2712221"],"award-info":[{"award-number":["S2712221"]}]},{"name":"Ministry of Small and Medium-sized Enterprises (SMEs) and Startups","award":["2021R1A6A1A03044501"],"award-info":[{"award-number":["2021R1A6A1A03044501"]}]},{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF)","award":["S2712221"],"award-info":[{"award-number":["S2712221"]}]},{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF)","award":["2021R1A6A1A03044501"],"award-info":[{"award-number":["2021R1A6A1A03044501"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Osteoporosis manifest in postmenopausal women is an osteolytic disease characterized by bone loss, leading to increased susceptibility to bone fractures and frailty. The use of complementary therapies to alleviate postmenopausal osteoporosis is fairly widespread among women. The current study examined that Pangasius hypophthalmus fish skin collagen hydrolysates (fsCH) inhibited ovariectomy (OVX)-induced bone loss by conducting inter-comparative experiments for anti-osteoporotic activity among 206\u2013618 mg\/kg fsCH, 2 mg\/kg isoflavone, 15 mg\/kg glycine\u2013proline\u2013hydroxyproline (GPH) tripeptide, and calcium lactate. Surgical estrogen loss of mice for 8 weeks reduced serum 17\u03b2-estradiol levels with uterus atrophy, which was ameliorated by orally administering fsCH or isoflavone to mice. Similar to isoflavone, fsCH containing GPH-enhanced bone mineral density reduced levels of cathepsin K and proton-handling proteins, and elevated collagen 1 level in OVX bones. The treatment with fsCH and isoflavone enhanced the serum levels of collagen synthesis-related procollagen type 1 carboxy\/amino-terminal propeptides reduced by OVX, whereas serum levels of osteocalcin and alkaline phosphatase, as well as collagen breakdown-related carboxy\/amino-terminal telopeptides of type 1 collagen were reduced in OVX mice treated with fsCH, isoflavone, and calcium lactate. The trabecular bones were newly formed in OVX bones treated with isoflavone and fsCH, but not with calcium lactate. However, a low-dose combination of fsCH and calcium lactate had a beneficial synergy effect on postmenopausal osteoporosis. Furthermore, similar to isoflavone, 15\u201370 \u03bcg\/mL fsCH, with its constituents of GPH and dipeptides of glycine\u2013proline and proline\u2013hydroxyproline, enhanced osteogenesis through stimulating differentiation, matrix mineralization, and calcium deposition of MC3T3-E1 osteoblasts. Accordingly, the presence of fsCH may encumber estrogen deficiency-induced bone loss through enhancing osteoclastogenic differentiation and matrix collagen synthesis. Therefore, fsCH may be a natural compound retarding postmenopausal osteoporosis and pathological osteoresorptive disorders.<\/jats:p>","DOI":"10.3390\/biomedicines10061382","type":"journal-article","created":{"date-parts":[[2022,6,11]],"date-time":"2022-06-11T09:33:26Z","timestamp":1654940006000},"page":"1382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dietary Collagen Hydrolysates Retard Estrogen Deficiency-Induced Bone Loss through Blocking Osteoclastic Activation and Enhancing Osteoblastic Matrix Mineralization"],"prefix":"10.3390","volume":"10","author":[{"given":"Soo-Il","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-185X","authenticated-orcid":false,"given":"Sin-Hye","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woojin","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Chul","family":"Shin","sequence":"additional","affiliation":[{"name":"Amicogen Inc., Healthcare & Nutrition Lab., Jinju 52840, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon-Sik","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Eun","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ae Hyang","family":"Kim","sequence":"additional","affiliation":[{"name":"Amicogen Inc., Healthcare & Nutrition Lab., Jinju 52840, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0314-5195","authenticated-orcid":false,"given":"Il-Jun","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2039-7968","authenticated-orcid":false,"given":"Young-Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5152\/eurjrheum.2016.048","article-title":"An overview and management of osteoporosis","volume":"4","year":"2017","journal-title":"Eur. J. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Joestl, J., Lang, N., Bukaty, A., Tiefenboeck, T.M., and Platzer, P. (2017). Osteoporosis associated vertebral fractures-health economic implications. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178209"},{"key":"ref_3","first-page":"9","article-title":"Primary osteoporosis in postmenopausal women","volume":"1","author":"Ji","year":"2015","journal-title":"Chronic Dis. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16069","DOI":"10.1038\/nrdp.2016.69","article-title":"Postmenopausal osteoporosis","volume":"2","author":"Eastell","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Qadir, A., Liang, S., Wu, Z., Chen, Z., Hu, L., and Qian, A. (2020). Senile osteoporosis: The involvement of differentiation and senescence of bone marrow stromal cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010349"},{"key":"ref_6","first-page":"21","article-title":"Principles of bone and joint disease control programs-osteoporosis","volume":"67","author":"Akesson","year":"2003","journal-title":"J. Rheumatol. Suppl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1185\/03007995.2011.643296","article-title":"Bisphosphonate therapy for osteoporosis: Combining optimal fracture risk reduction with patient preference","volume":"28","author":"Beard","year":"2012","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"V59","DOI":"10.1359\/jbmr.07s209","article-title":"Therapy of osteoporosis with calcium and vitamin D","volume":"22","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jphs.2015.08.003","article-title":"Daily intake of \u03b2-cryptoxanthin prevents bone loss by preferential disturbance of osteoclastic activation in ovariectomized mice","volume":"129","author":"Ozaki","year":"2015","journal-title":"J. Pharmacol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yee, M.M.F., Chin, K.Y., Ima-Nirwana, S., and Wong, S.K. (2021). Vitamin a and bone health: A review on current evidence. Molecules, 26.","DOI":"10.3390\/molecules26061757"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.steroids.2014.12.010","article-title":"Estrogen and bone health in men and women","volume":"99 Pt A","author":"Cauley","year":"2015","journal-title":"Steroids"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"326","DOI":"10.26444\/aaem\/135529","article-title":"Assessment of the effect of estradiol on biochemical bone turnover markers among postmenopausal women","volume":"28","author":"Jamka","year":"2021","journal-title":"Ann. Agric. Environ. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/j.1600-0412.2012.01473.x","article-title":"New developments in the treatment of osteoporosis","volume":"92","author":"Eriksen","year":"2013","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_14","first-page":"443","article-title":"How to manage postmenopausal osteoporosis?","volume":"66","author":"Body","year":"2011","journal-title":"Acta Clin. Belg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s10549-020-05744-w","article-title":"Hormone replacement therapy and mammographic density: A systematic literature review","volume":"182","author":"Azam","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s11914-019-00549-3","article-title":"Update on menopausal hormone therapy for fracture prevention","volume":"17","author":"Stepan","year":"2019","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1185\/03007995.2013.763779","article-title":"Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis","volume":"29","author":"Josse","year":"2013","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1210\/er.2015-1114","article-title":"Cathepsin K inhibitors for osteoporosis: Biology, potential clinical utility, and lessons learned","volume":"38","author":"Drake","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jsbmb.2012.12.004","article-title":"The pros and cons of plant estrogens for menopause","volume":"139","author":"Bedell","year":"2014","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"154","DOI":"10.4103\/0976-9668.92322","article-title":"Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapeutic choices: An overview","volume":"2","author":"Qureshi","year":"2011","journal-title":"J. Nat. Sci. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1002\/jps.20987","article-title":"Molecular aspects of phytoestrogen selective binding at estrogen receptors","volume":"96","author":"Turner","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1021\/jf021114s","article-title":"Evaluation of the estrogenic effects of legume extracts containing phytoestrogens","volume":"51","author":"Wiese","year":"2003","journal-title":"J. Agric. Food Chem."},{"key":"ref_23","first-page":"457052","article-title":"Effect of formononetin on mechanical properties and chemical composition of bones in rats with ovariectomy-induced osteoporosis","volume":"2013","author":"Wojnar","year":"2013","journal-title":"Evid. Based Compl. Alternat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.phymed.2014.04.002","article-title":"Phloretin promotes osteoclast apoptosis in murine macrophages and inhibits estrogen deficiency-induced osteoporosis in mice","volume":"21","author":"Lee","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s00223-012-9584-7","article-title":"(-)-Epigallocathechin-3-gallate, an AMPK activator, decreases ovariectomy-induced bone loss by suppression of bone resorption","volume":"90","author":"Lee","year":"2012","journal-title":"Calcif. Tissue Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1097\/GME.0b013e31828244f0","article-title":"(-)-Epigallocatechin-3-gallate improves bone microarchitecture in ovariectomized rats","volume":"20","author":"Chen","year":"2013","journal-title":"Menopause"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"919374","DOI":"10.1155\/2013\/919374","article-title":"Antiosteoclastic activity of milk thistle extract after ovariectomy to suppress estrogen deficiency-induced osteoporosis","volume":"2013","author":"Kim","year":"2013","journal-title":"Biomed Res. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17332","DOI":"10.1038\/s41598-017-17427-6","article-title":"Artemisia annua extract prevents ovariectomy-induced bone loss by blocking receptor activator of nuclear factor kappa-B ligand-induced differentiation of osteoclasts","volume":"7","author":"Lee","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41419-021-03939-7","article-title":"A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-kappaB pathways","volume":"12","author":"Liu","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.bbrc.2020.03.177","article-title":"Inhibition of RIPK1\/RIPK3 ameliorates osteoclastogenesis through regulating NLRP3-dependent NF-kappaB and MAPKs signaling pathways","volume":"526","author":"Liang","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1053\/sarh.2000.9622","article-title":"Role of collagen hydrolysate in bone and joint disease","volume":"30","author":"Moskowitz","year":"2000","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_32","first-page":"1922","article-title":"Biological effect of hydrolyzed collagen on bone metabolism","volume":"57","author":"Daneault","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.maturitas.2009.10.002","article-title":"Effect of dietary supplementation with collagen hydrolysates on bone metabolism of postmenopausal women with low mineral density","volume":"65","author":"Morais","year":"2010","journal-title":"Maturitas"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kang, M.K., Kim, D.Y., Oh, H., Kim, S.I., Oh, S.Y., Na, W., Park, S.H., Park, K., Kim, J.I., and Kim, A.H. (2021). Dietary collagen hydrolysates ameliorate furrowed and parched skin caused by photoaging in hairless mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116137"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1021\/acs.jafc.6b05679","article-title":"Oral ingestion of collagen hydrolysate leads to the transportation of highly concentrated Gly-Pro-Hyp and its hydrolyzed form of Pro-Hyp into the bloodstream and skin","volume":"65","author":"Yazaki","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/psc.870","article-title":"Transport of a tripeptide, Gly-Pro-Hyp, across the porcine intestinal brush-border membrane","volume":"13","author":"Lackeyram","year":"2007","journal-title":"J. Pept. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.bone.2009.07.091","article-title":"Rapid and robust response of biochemical markers of bone formation to teriparatide therapy","volume":"45","author":"Glover","year":"2009","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1097\/BCO.0b013e3282630851","article-title":"The role of alkaline phosphatase in mineralization","volume":"18","author":"Golub","year":"2007","journal-title":"Curr. Opin. Orthop."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1002\/jbmr.5650070613","article-title":"Distinct proliferative and differentiation stages of murine MC3T3-E1 cells in culture: An in vitro model of osteoblast development","volume":"7","author":"Quarles","year":"1992","journal-title":"J. Bone Miner. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lee, E.J., Na, W., Kang, M.K., Kim, Y.H., Kim, D.Y., Oh, H., Kim, S.I., Oh, S.Y., Park, S., and Park, K. (2021). Hydroxycoumarin scopoletin inhibits bone loss through enhancing induction of bone turnover markers in a mouse model of type 2 diabetes. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060648"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1006\/cbir.1994.1088","article-title":"Why does bone matrix contain non-collagenous proteins? The possible roles of osteocalcin, osteonectin, osteopontin and bone sialoprotein in bone mineralisation and resorption","volume":"18","author":"Roach","year":"1994","journal-title":"Cell. Biol. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jdsr.2009.10.003","article-title":"Molecular mechanisms of BMP-induced bone formation: Cross-talk between BMP and NF-\u03baB signaling pathways in osteoblastogenesis","volume":"46","author":"Jimi","year":"2010","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Na, W., Kang, M.K., Park, S.H., Kim, D.Y., Oh, S.Y., Oh, M.S., Park, S., Kang, I.J., and Kang, Y.H. (2021). Aesculetin accelerates osteoblast differentiation and matrix-vesicle-mediated mineralization. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212391"},{"key":"ref_44","first-page":"iv2","article-title":"Structural basis of growth-related gain and age-related loss of bone strength","volume":"47","author":"Seeman","year":"2008","journal-title":"Rheumatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jsbmb.2013.09.008","article-title":"Prevention and treatment of postmenopausal osteoporosis","volume":"142","author":"Tella","year":"2014","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1089\/jwh.2017.6706","article-title":"Postmenopausal osteoporosis: A clinical review","volume":"27","author":"Watts","year":"2018","journal-title":"J. Womens Health"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.3892\/etm.2021.10815","article-title":"Osteoporosis therapies and their mechanisms of action (Review)","volume":"22","author":"Kim","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1177\/1759720X10392105","article-title":"Medical treatment of osteoporotic vertebral fractures","volume":"3","author":"Langdahl","year":"2011","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/j.1542-2011.2011.00135.x","article-title":"Osteoporosis update","volume":"56","author":"Schuiling","year":"2011","journal-title":"J. Midwifery Womens Health"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1006\/jsbi.1998.3977","article-title":"Gly-X-Y tripeptide frequencies in collagen: A context for host-guest triple-helical peptides","volume":"122","author":"Ramshaw","year":"1998","journal-title":"J. Struct. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11914-996-0011-8","article-title":"Combination\/sequential therapy in osteoporosis","volume":"2","author":"Lecart","year":"2004","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"115516","DOI":"10.1016\/j.bone.2020.115516","article-title":"Treatment of postmenopausal osteoporosis with bone-forming and antiresorptive treatments: Combined and sequential approaches","volume":"139","author":"Langdahl","year":"2020","journal-title":"Bone"}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1382\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:28:00Z","timestamp":1760138880000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,10]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biomedicines10061382"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines10061382","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,10]]}}}