Transforming growth factor-beta induces osteoclast ruffling and chemotaxis: potential role in osteoclast recruitment.
Transforming growth factor-beta (TGF-beta) is released from the matrix during bone resorption and has been implicated in the pathogenesis of giant cell tumors of bone and the expansion of breast cancer metastases in bone. Because osteoclasts mediate tumor-induced osteolysis, we investigated whether TGF-beta stimulates osteoclast recruitment. Osteoclasts were isolated from rat long bones and time-lapse video microscopy was used to monitor their morphology and motility. Within 5 minutes, TGF-beta (0.1 nM) induced dynamic ruffling, with 65% of osteoclasts displaying membrane ruffles compared with 35% in untreated controls. Over a 2-h period, osteoclasts exhibited significant directed migration toward a source of TGF-beta, indicating chemotaxis. echistatin, an alphavbeta3 integrin blocker that inhibits macrophage colony-stimulating factor (M-CSF)-induced osteoclast migration, did not prevent the migration of osteoclasts toward TGF-beta. In contrast, a beta1 integrin blocking antibody inhibited osteoclast chemotaxis toward TGF-beta but not M-CSF. These data indicate the selective use of integrins by osteoclasts migrating in response to different chemotaxins. In addition, wortmannin and U0126 inhibited TGF-beta-induced chemotaxis, suggesting involvement of the phosphatidylinositol 3 (PI 3) kinase and mitogen-activated protein (MAP) kinase signaling pathways. Physiologically, TGF-beta, may coordinate osteoclast activity by recruiting osteoclasts to existing sites of resorption. Pathologically, TGF-beta-induced osteoclast recruitment may be critical for expansion of primary and metastatic tumors in bone.
Pilkington
M F
MF
Department of Physiology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Sims
S M
SM
Dixon
S J
SJ
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005269:Femur / Q000166:cytology / Q000187:drug effects; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018715:Microscopy, Video; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D010455:Peptides / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013977:Tibia / Q000166:cytology / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D004791:Enzyme Inhibitors; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; D010455:Peptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016212:Transforming Growth Factor beta; C113580:U 0126; C057986:echistatin; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin