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

• Published in: Journal of bone and mineral research 2000-03, Vol.15 (3), p.466-473
• Main Authors: Kawaguchi, Hiroshi, Chikazu, Daichi, Nakamura, Kozo, Kumegawa, Masayoshi, Hakeda, Yoshiyuki
• Format: Article
• Language: English
• Subjects: Acid Phosphatase - analysis; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Biomarkers; bone; Bone Marrow Cells - physiology; Bone Resorption - metabolism; Bone Resorption - pathology; Calcium - metabolism; Cells, Cultured - drug effects; Coculture Techniques; cyclooxygenase; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dentin - drug effects; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; Etodolac - pharmacology; fibroblast growth factor; Fibroblast Growth Factor 2 - pharmacology; Flurbiprofen - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Indomethacin - pharmacology; Isoenzymes - analysis; Isoenzymes - biosynthesis; Isoenzymes - genetics; Membrane Proteins; Mice; Nitrobenzenes - pharmacology; Osteoblasts - drug effects; Osteoblasts - metabolism; osteoclast; Osteoclasts - drug effects; Osteoclasts - metabolism; prostaglandin; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandins - biosynthesis; Rabbits; RNA, Messenger - biosynthesis; Skeleton and joints; Skull - cytology; Space life sciences; Sulfonamides - pharmacology; Tartrate-Resistant Acid Phosphatase; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2000.15.3.466

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.