Recombinant human transforming growth factor-alpha stimulates the formation of osteoclast-like cells in long-term human marrow cultures

• Published in: The Journal of clinical investigation 1986-10, Vol.78 (4), p.894-898
• Main Authors: TAKAHASHI, N, MACDONALD, B. R, HON, J, WINKLER, M. E, DERYNCK, R, MUNDY, G. R, ROODMAN, G. D
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow Cells; Calcitriol - pharmacology; Cell physiology; Cells, Cultured; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Epidermal Growth Factor - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Molecular and cellular biology; Osteoclasts - drug effects; Peptides - pharmacology; Recombinant Proteins - pharmacology; Responses to growth factors, tumor promotors, other factors; Time Factors; Transforming Growth Factors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI112677

Transforming growth factor-alpha (TGF-alpha) is synthesized by a variety of tumor cell lines and stimulates osteoclastic bone resorption in vitro. The mechanism by which TGF-alpha increases osteoclast activity is unknown. We used a human marrow culture system that forms osteoclast-like multinucleated cells (MNCs) to determine the effects of recombinant human TGF-alpha on MNC formation. Addition of 0.01 ng/ml TGF-alpha for the 1st week followed by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for the subsequent 2 wk significantly increased MNCs. Treatment of these cultures with TGF-alpha without later addition of 1,25(OH)2D3 did not increase MNC formation. Autoradiographic studies revealed that TGF-alpha stimulated proliferation of precursors for MNCs, and 1,25(OH)2D3 increased their rate of fusion into MNCs. Addition of murine epidermal growth factor (EGF) (0.1 ng/ml) followed by 1,25(OH)2D3 also significantly stimulated MNC formation. These data suggest that TGF-alpha and EGF may stimulate bone resorption by increasing the proliferation of osteoclast precursors, which leads to increased numbers of osteoclasts.