乳铁蛋白（Lf）是一种内源性合成的多功能蛋白质，具有免疫调节、抗菌、抗病毒和抗癌等多种生物学作用。最近的研究揭示了Lf在骨重塑中的重要功能，它能调节成骨细胞、软骨细胞、破骨细胞和间充质干细胞的功能。参与Lf信号通路的信号分子包括低密度脂蛋白受体相关蛋白-1（LRP-1）、转化生长因子β（TGF-β）和胰岛素样生长因子-1（IGF-1），它们能激活ERK、PI3K/Akt和NF-κB等下游通路。这些通路共同刺激成骨细胞的增殖、分化和骨化过程，同时抑制破骨细胞的分化和活性。此外，Lf对核因子kappa B（NF-κB）的抑制作用能直接抑制破骨细胞的形成和活性。Lf还通过激活线粒体活化蛋白激酶/外周信号调节激酶（MAPK/ERK）和磷酸肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路，促进软骨祖细胞的增殖和分化为软骨细胞，并通过抑制NF-κB通路抑制基质降解酶的表达。Lf促进了成骨细胞和软骨细胞的活性，抑制了破骨细胞的功能，加速骨折修复的过程。此外，研究表明，Lf能够通过促进骨形成和抑制骨吸收来纠正骨质疏松症中紊乱的骨重塑。Lf在骨健康方面的这些有益效应已经引起了在营养保健品和制药领域中的探索。然而，由于Lf分子较大，小型生物活性肽在制药应用中更为常见。这些肽已经在动物研究中证明能促进骨折修复和逆转骨质疏松症，显示出作为骨相关疾病治疗药物的潜力。然而，血清中Lf的有效浓度可能无法在需要骨再生的部位达到足够的水平，因此需要开发各种给药策略来提高Lf的生物利用度，并将Lf的活性浓度定位到需要骨再生的部位。本综述对上述问题进行了批判性讨论，揭示了Lf在骨重塑中的作用以及Lf作为骨疾病治疗靶标的潜力。版权所有© 2023 Tian, Han, Yang, Li, Shi and Tian.

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's critical functions in bone remodeling, where it regulates the function of osteoblasts, chondrocytes, osteoclasts, and mesenchymal stem cells. The signaling pathways involved in Lf's signaling in osteoblasts include (low density lipoprotein receptor-related protein - 1 (LRP-1), transforming growth factor β (TGF-β), and insulin-like growth factor - 1 (IGF-1), which activate downstream pathways such as ERK, PI3K/Akt, and NF-κB. These pathways collectively stimulate osteoblast proliferation, differentiation, and mineralization while inhibiting osteoclast differentiation and activity. Additionally, Lf's inhibitory effect on nuclear factor kappa B (NF-κB) 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-κB pathway. Lf's 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's 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.Copyright © 2023 Tian, Han, Yang, Li, Shi and Tian.