Direct and Indirect Actions of Fibroblast Growth Factor 2 on Osteoclastic Bone Resorption in Cultures

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  • Hiroshi Kawaguchi
    Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
  • Daichi Chikazu
    Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
  • Kozo Nakamura
    Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
  • Masayoshi Kumegawa
    Department of Oral Anatomy, School of Dentistry, Meikai University, Saitama, Japan
  • Yoshiyuki Hakeda
    Department of Oral Anatomy, School of Dentistry, Meikai University, Saitama, Japan

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<jats:title>Abstract</jats:title> <jats:p>Fibroblast growth factor 2 (FGF-2 or basic FGF) is known to show variable actions on bone formation and bone resorption. This study was undertaken to elucidate the mechanisms whereby FGF-2 affects bone metabolism, especially bone resorption, using three different culture systems. FGF-2 at 10−9 M and higher concentrations induced osteoclastic cell formation in the coculture system of mouse osteoblastic cells and bone marrow cells, and this induction was abrogated by nonsteroidal anti-inflammatory drugs (NSAIDs). 45Ca release from prelabeled cultured mouse calvariae stimulated by FGF-2 (10−8 M) was also inhibited by NSAIDs, and the inhibition was stronger by NSAIDs, which are more selective for inhibition of cyclooxygenase 2 (COX-2) than COX-1, suggesting the mediation of COX-2 induction. COX-2 was highly expressed and its messenger RNA (mRNA) level was stimulated by FGF-2 in osteoblastic cells whereas it was undetectable or not stimulated by FGF-2 in cells of osteoclast lineage. To further investigate the direct actions of FGF-2 on osteoclasts, resorbed pit formation was compared between cultures of purified osteoclasts and unfractionated bone cells from rabbit long bones. FGF-2 (≥10−12 M) stimulated resorbed pit formation by purified osteoclasts with a maximum effect of 2.0-fold at 10−11 M, and no further stimulation was observed at higher concentrations. However, FGF-2 at 10−9 M − 10−8 M stimulated resorbed pit formation by unfractionated bone cells up to 9.7-fold. NS-398, a specific COX-2 inhibitor, did not affect the FGF-2 stimulation on purified osteoclasts but inhibited that on unfractionated bone cells. We conclude that FGF-2 at low concentrations (≥10−12 M) acts directly on mature osteoclasts to resorb bone moderately, whereas at high concentrations (≥10−9 M) it acts on osteoblastic cells to induce COX-2 and stimulates bone resorption potently.</jats:p>

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