Lactoferrin Is a Potent Regulator of Bone Cell Activity and Increases Bone Formation in Vivo

Abstract

Lactoferrin is an iron-binding glycoprotein present in epithelial secretions, such as milk, and in the secondary granules of neutrophils. We found it to be present in fractions of milk protein that stimulated osteoblast growth, so we assessed its effects on bone cell function. Lactoferrin produced large, dose-related increases in thymidine incorporation in primary or cell line cultures of human or rat osteoblast-like cells, at physiological concentrations (1-100 microg/ml). Maximal stimulation was 5-fold above control. Lactoferrin also increased osteoblast differentiation and reduced osteoblast apoptosis by up to 50-70%. Similarly, lactoferrin stimulated proliferation of primary chondrocytes. Purified, recombinant, human, or bovine lactoferrins had similar potencies. In mouse bone marrow cultures, osteoclastogenesis was dose-dependently decreased and was completely arrested by lactoferrin, 100 microg/ml, associated with decreased expression of receptor activator of nuclear factor-kappaB ligand. In contrast, lactoferrin had no effect on bone resorption by isolated mature osteoclasts. Lactoferrin was administered over calvariae of adult mice for 5 d. New bone formation, assessed using fluorochrome labels, was increased 4-fold by a 4-mg dose of lactoferrin. Thus, lactoferrin has powerful anabolic, differentiating, and antiapoptotic effects on osteoblasts and inhibits osteoclastogenesis. Lactoferrin is a potential therapeutic target in bone disorders such as osteoporosis and is possibly an important physiological regulator of bone growth.

Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway

“…Previous studies have shown that lactoferrin has an anabolic effect on osteoblasts and osteoclasts in vitro [8,9,11] . The aim of this study was to evaluate the changes induced by lactoferrin in the Ovx rat model and to identify the pathways that mediate the anabolic action of lactoferrin in bone.…”

“…LF has also been shown to have an inhibitory effect on osteoclast formation [11] . Locally injecting LF above the hemicalvaria in adult mice for 5 successive days resulted in increased bone formation and bone area compared with the controls [8] . In addition, oral LF administered to Ovx rats for 3 months protected against Ovx-induced decreases in bone volume and mineral density npg and led to increased mechanical strength parameters [14] .…”

“…Many studies have demonstrated that lactoferrin has antimicrobial activity and functions as a regulator of immune response [6,7] . In recent years, several studies have shown that LF acts as a growth factor and has both in vitro and in vivo anabolic activity in bone [8][9][10][11][12] . Lactoferrin induces the proliferation and differentiation of osteoblast-like cells and inhibits osteoclastogenesis in vitro [10,13] .…”

Recombinant human lactoferrin expressed in glycoengineered Pichia pastoris: effect of terminal N-acetylneuraminic acid on in vitro secondary humoral immune response

“…Interestingly, LF could partially reconstitute the cellular immune response in MTX-treated mice, but not the primary humoral immune response in vivo [1]. It can further be hypothesized that memory T helper cells, responsible for development of the secondary immune response are less prone to apoptosis [40], coinciding well with lactoferrin's anti-apoptotic properties [9,34,45]. LF could prevent MTX-induced suppression in several ways, including the induction of specific cytokines in sialoadhesin-positive splenocytes.…”

Lactoferrin inhibits apoptosis through insulin-like growth factor I in primary rat osteoblasts

“…Previous studies have shown anabolic effects of bLF on osteoblasts and osteoclasts in vitro [4,8,9] . Grey found that bLF inhibited 50%-70% of apoptosis in osteoblasts, but he also discovered that this inhibition did not involve the PI3 kinase or p42/44 MAP kinase signaling pathways [4] .…”