Editors' ChoiceBONE

Does Heparin BMP Up Bone Formation?

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Science's STKE  15 Aug 2006:
Vol. 2006, Issue 348, pp. tw278
DOI: 10.1126/stke.3482006tw278

Bone morphogenetic proteins (BMPs), growth factors involved in bone and cartilage development, promote bone regeneration in vivo. In humans, however, large concentrations of BMP are required to stimulate clinically useful bone formation. Zhao et al. investigated the mechanism whereby heparin enhances BMP-mediated osteoblastic differentiation in a model system in vitro in which BMP inhibits myogenic differentiation and promotes osteoblastic differentiation and whether heparin promoted BMP activity in vivo. Heparin enhanced the ability of BMP-2 and BMP-4 to promote alkaline phosphatase activity (a marker of osteoblastic differentiation) in cultured C2C12 myoblasts, although it suppressed osteoblastic differentiation in response to BMP-6. In the absence of heparin, BMP-2 treatment elicited an increase in Smad phosphorylation that peaked within an hour and then gradually decreased. Heparin had no effect on BMP-2-dependent Smad phosphorylation within the first 12 hours of BMP-2 exposure, but it increased Smad phosphorylation at 24 and 48 hours. Similarly, a BMP-2 dependent increase in the expression of mRNA encoding the BMP antagonist noggin was unaffected by heparin at 1 hour but was increased by heparin at 72 hours. However, heparin blocked noggin-dependent inhibition of BMP-2. In the absence of heparin, BMP-2 in the culture medium decreased to less than half the initial concentration within 1 hour and had nearly vanished after 10 hours. Heparin inhibited this decline so that more than 60% of the initial concentration of BMP-2 was present at 12 hours and substantial BMP-2 was detectable at 50 hours. Moreover, heparin enhanced BMP-dependent formation of ectopic bone in mice, increasing both the amount and the density of bone formed. Thus, the authors conclude that heparin might provide a useful clinical adjunct to BMP and that it acts by protecting BMP from degradation and from the effects of antagonists.

B. Zhao, T. Katagiri, H. Toyoda, T. Takada, T. Yanai, T. Fukuda, U. I. Chung, T. Koike, K. Takaoka, R. Kamijo, Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2. J. Biol. Chem. 281, 23246-23253 (2006). [PubMed]

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