{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T14:26:56Z","timestamp":1792160816739,"version":"4.4.0"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T00:00:00Z","timestamp":1692748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Lactoferrin (Lf) is a multifunctional protein that is synthesized endogenously and has various biological roles including immunological regulation, antibacterial, antiviral, and anticancer properties. Recently, research has uncovered Lf\u2019s critical functions in bone remodeling, where it regulates the function of osteoblasts, chondrocytes, osteoclasts, and mesenchymal stem cells. The signaling pathways involved in Lf\u2019s signaling in osteoblasts include (low density lipoprotein receptor-related protein \u2013 1 (LRP-1), transforming growth factor \u03b2 (TGF-\u03b2), and insulin-like growth factor \u2013 1 (IGF-1), which activate downstream pathways such as ERK, PI3K\/Akt, and NF-\u03baB. These pathways collectively stimulate osteoblast proliferation, differentiation, and mineralization while inhibiting osteoclast differentiation and activity. Additionally, Lf\u2019s inhibitory effect on nuclear factor kappa B (NF-\u03baB) suppresses the formation and activity of osteoclasts directly. Lf also promotes chondroprogenitor proliferation and differentiation to chondrocytes by activating the mitogen-activated protein kinase\/extracellular signal-regulated kinase (MAPK\/ERK) and phosphoinositide 3-kinase\/protein kinase B(PI3K\/Akt)signaling pathways while inhibiting the expression of matrix-degrading enzymes through the suppression of the NF-\u03baB pathway. Lf\u2019s ability to stimulate osteoblast and chondrocyte activity and inhibit osteoclast function accelerates fracture repair, as demonstrated by its effectiveness in animal models of critical-sized long bone defects. Moreover, studies have indicated that Lf can rescue dysregulated bone remodeling in osteoporotic conditions by stimulating bone formation and suppressing bone resorption. These beneficial effects of Lf on bone health have led to its exploration in nutraceutical and pharmaceutical applications. However, due to the large size of Lf, small bioactive peptides are preferred for pharmaceutical applications. These peptides have been shown to promote bone fracture repair and reverse osteoporosis in animal studies, indicating their potential as therapeutic agents for bone-related diseases. Nonetheless, the active concentration of Lf in serum may not be sufficient at the site requiring bone regeneration, necessitating the development of various delivery strategies to enhance Lf\u2019s bioavailability and target its active concentration to the site requiring bone regeneration. This review provides a critical discussion of the issues mentioned above, providing insight into the roles of Lf in bone remodeling and the potential use of Lf as a therapeutic target for bone disorders.<\/jats:p>","DOI":"10.3389\/fendo.2023.1218148","type":"journal-article","created":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T19:38:22Z","timestamp":1692819502000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["The role of lactoferrin in bone remodeling: evaluation of its potential in targeted delivery and treatment of metabolic bone diseases and orthopedic conditions"],"prefix":"10.3389","volume":"14","author":[{"given":"Miao","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-bo","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-yun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-long","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-sai","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2021.101551","article-title":"Menopausal hormone therapy for the management of osteoporosis","volume":"35","author":"Gosset","year":"2021","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","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":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0809493","article-title":"Denosumab for prevention of fractures in postmenopausal women with osteoporosis","volume":"361","author":"Cummings","year":"2009","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ejphar.2018.02.028","article-title":"Targeted inhibition of sclerostin for post-menopausal osteoporosis therapy: A critical assessment of the mechanism of action","volume":"826","author":"Bhattacharyya","year":"2018","journal-title":"Eur J Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003-1307","article-title":"Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo","volume":"145","author":"Cornish","year":"2004","journal-title":"Endocrinology"},{"key":"B6","article-title":"Lactoferrin: A general review","volume":"80","author":"Levay","year":"1995","journal-title":"Haematologica"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4165(83)90317-3","article-title":"The effect of trypsin and chymotrypsin on the in vitro antimicrobial and iron-binding properties of lactoferrin in human milk and bovine colostrum. 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