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J. Biol. Chem., Vol. 279, Issue 18, 18361-18369, April 30, 2004

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Release of Intact and Fragmented Osteocalcin Molecules from Bone Matrix during Bone Resorption in Vitro^*

Kaisa K. Ivaska, Teuvo A. Hentunen, Jukka Vääräniemi, Hannele Ylipahkala, Kim Pettersson¶, and H. Kalervo Väänänen

From the Institute of Biomedicine, Department of Anatomy, and the ^¶Department of Biotechnology, University of Turku, FIN-20520 Turku, Finland

Osteocalcin detected from serum samples is considered a specific marker of osteoblast activity and bone formation rate. However, osteocalcin embedded in bone matrix must also be released during bone resorption. To understand the contribution of each type of bone cell in circulating osteocalcin levels, we used immunoassays detecting different molecular forms of osteocalcin to monitor bone resorption in vitro. Osteoclasts were obtained from rat long bones and cultured on bovine bone slices using osteocalcin-depleted fetal bovine serum. In addition, human osteoclasts differentiated from peripheral blood mononuclear cells were used. Both rat and human osteoclasts released osteocalcin from bovine bone into medium. The amount of osteocalcin increased in the presence of parathyroid hormone, a stimulator of resorption, and decreased in the presence of bafilomycin A1, an inhibitor of resorption. The amount of osteocalcin in the medium correlated with a well characterized marker of bone resorption, the C-terminal telopeptide of type I collagen (r > 0.9, p < 0.0001). The heterogeneity of released osteocalcin was determined using reverse phase high performance liquid chromatography, and several molecular forms of osteocalcin, including intact molecule, were identified in the culture medium. In conclusion, osteocalcin is released from the bone matrix during bone resorption as intact molecules and fragments. In addition to the conventional use as a marker of bone formation, osteocalcin can be used as a marker of bone resorption in vitro. Furthermore, bone matrix-derived osteocalcin may contribute to circulating osteocalcin levels, suggesting that serum osteocalcin should be considered as a marker of bone turnover rather than bone formation.

Received for publication, December 31, 2003 , and in revised form, February 12, 2004.

^* This work was supported by funds from the National Graduate School for Musculoskeletal Diseases, the Academy of Finland, and the Sigrid Juselius Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Institute of Biomedicine, Dept. of Anatomy, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Tel.: 358-2-333-7970; Fax: 358-2-333-7352; E-mail: kaisa.ivaska{at}utu.fi.

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