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Endocrinology Vol. 145, No. 9 4366-4374
Copyright © 2004 by The Endocrine Society

Lactoferrin Is a Potent Regulator of Bone Cell Activity and Increases
Bone Formation in Vivo
Jillian Cornish, Karen E. Callon, Dorit Naot, Kate P. Palmano, Tatjana
Banovic, Usha Bava, Maureen Watson, Jian-Ming Lin, P. C. Tong, Qi Chen,
Vincent A. Chan, Helen E. Reid, Nick Fazzalari, Heather M. Baker,
Edward N. Baker, Neill W. Haggarty, Andrew B. Grey and Ian R. Reid
Department of Medicine (J.C., K.E.C., D.N., T.B., U.B., M.W., J.-M.L.,
P.C.T., Q.C., V.A.C., H.E.R., A.B.G., I.R.R.) and School of Biological
Sciences (H.M.B., E.N.B.), University of Auckland, Auckland 1001, New
Zealand; Fonterra Research Centre (K.P.P., N.W.H.), Palmerston North
5315, New Zealand; and Institute of Medical and Veterinary Science
(N.F.), Adelaide 5000, Australia

Address all correspondence and requests for reprints to: Dr. J.
Cornish, Department of Medicine, University of Auckland, Private Bag
92019, Auckland 1001, New Zealand. E-mail: j.cornish@auckland.ac.nz.

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
µg/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 µg/ml, associated with decreased
expression of receptor activator of nuclear factor-B 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.

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Copyright © 2004 by The Endocrine Society