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Hormonal Regulation of the Production of Collagenase and a Collagenase Inhibitor Activity by Rat Osteogenic Sarcoma Cells^*

N. C. PARTRIDGE, J. J. JEFFREY, L. S. EHLICH, S. L. TEITELBAUM, C. FLISZAR, H. G. WELGUS and A. J. KAHN

Pediatric Research Institute, Cardinal Glennon Children's Hospital, and St. Louis University (N.C.P., A.J.K.); and the Division of Dermatology, Washington University School of Medicine (J.J.J., L.S.E.), and the Division of Dermatology (C.F., H.G. W.) and the Department of Pathology (S.L.T.), Jewish Hospital at Washington University Medical Center St. Louis, Missouri 63110
Shriners Hospitals for Crippled Children, St. Louis Unit St. Louis, Missouri63131 (S.L.T.)

Address all correspondence and requests for reprints to: Dr. N. C. Partridge, Pediatric Research Institute, 3662 Park Avenue, St. Louis, Missouri 63110.

Abstract

Collagenases that specifically cleave native collagen at neutral pH have been implicated in the maintenance and turnover of connective tissue. In bone, the origin of neutral collagenase has remained equivocal, although recent studies have indicated that it is synthesized by the osteoblast. In the present work, regulation of secretion of neutral collagenase and a collagenase inhibitory activity was investigated using the osteoblastic tumor cell line UMR 106-01 and a variety of bone-resorbing agents. Under basal conditions, UMR 106-01 cells produced very low levels of collagenase but substantial amounts of the inhibitory activity. Exposure to PTH and, to a lesser extent, 1,25-dihydroxyvitamin D₃, prostaglandin E₂, retinoic acid, and epidermal growth factor stimulated the release of collagenase, an effect not seen with interleukin-1 or heparin. The stimulation of collagenase by PTH was dose dependent, with a half-maximal response occurring at 10^-8 M. Inclusion of isobutylmethylxanthine decreased the concentration of PTH required to produce half-maximal stimulation to 2 x 10^-10 M, indicating action via cAMP. With respect to the inhibitory activity, PTH and epidermal growth factor were the only agents, among those tested, able to enhance its production. Both hormones caused a 50–100% increase over control levels 72 h after hormone administration. There were notable differences in the time courses of production of collagenase and the inhibitor. After treatment with PTH, the enzyme reached maximal concentrations between 12–48 h, but declined to undetectable levels by 96 h. In contrast, the inhibitory activity was secreted in a linear fashion, with the highest concentrations achieved around 72–96 h. These results suggest a complex pattern of regulation of collagenase and inhibitor secretion by the osteoblastic cell, with the steady accumulation of inhibitor perhaps being responsible for the ultimate curtailment of enzyme activity. (Endocrinology 120: 1956–1962,1987)

Footnotes

^* This work was supported by USPHS Grants HD-05291, AM-32788, and AM-35805 and the Shriners Hospitals for Crippled Children (Project 15959).

C. J. Martin Fellow of the National Health and Medical Research Council of Australia.

Received May 16, 1986.

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