Endocrinology, Vol 136, 1348-1354, Copyright © 1995 by Endocrine Society

ARTICLES

Insulin-like growth factors inhibit interstitial collagenase synthesis in bone cell cultures

E Canalis, S Rydziel, AM Delany, S Varghese and JJ Jeffrey
Department of Research, St. Francis Hospital and Medical Center, Hartford, Connecticut 06105.

Insulin-like growth factor-I (IGF-I) and IGF-II are among the most prevalent growth factors secreted by bone cells and are presumed to act as autocrine regulators of bone formation. We recently demonstrated that IGFs inhibit bone collagen degradation, and we postulated that they may either inhibit the expression of interstitial collagenase or stimulate the synthesis of tissue inhibitors of metalloproteinase-1 (TIMP-1), -2, or -3. We tested the effects of IGF-I and -II on collagenase and TIMP-1, -2, and -3 expression in cultures of osteoblast- enriched cells from 22-day-old fetal rat calvariae (Ob cells). Steady state messenger RNA (mRNA) levels were determined by Northern blot analysis, and collagenase concentrations were determined in the culture medium by a specific immunoassay. After 2-6 h of treatment, IGF-I and - II decreased collagenase transcripts by up to 80%. IGF-I was a more potent inhibitor than IGF-II, because it was active at doses as low as 10 nM, whereas a dose of 100 nM was required to observe the IGF-II effect. In addition, IGF-I and -II opposed the stimulatory effect of retinoic acid on collagenase transcripts. Immunoreactive collagenase levels were not detectable in control or IGF-treated cultures, but IGF- I and -II decreased the levels induced by retinoic acid by 70-90%. The protein synthesis inhibitor cycloheximide superinduced collagenase transcripts, and IGF-I or -II decreased this mRNA induction to levels similar to, but not lower than, those observed in control cultures. The effects of IGF-I and -II on collagenase transcripts were not modified by the DNA synthesis inhibitor hydroxyurea at 1 mM. Neither IGF-I nor IGF-II modified the expression of TIMP-1, -2, or -3 mRNA in Ob cells. TIMP protein levels were not determined, and our study does not exclude a translational or posttranslational effect of IGF. In conclusion, IGF- I and -II decrease interstitial collagenase transcripts as well as induced protease levels in Ob cells, and this effect may contribute to their inhibitory actions on bone collagen degradation.

This article has been cited by other articles:

				A. M. Delany, D. Durant, and E. Canalis Glucocorticoid Suppression of IGF I Transcription in Osteoblasts Mol. Endocrinol., October 1, 2001; 15(10): 1781 - 1789. [Abstract] [Full Text] [PDF]

				W Hui, A D Rowan, and T Cawston Insulin-like growth factor 1 blocks collagen release and down regulates matrix metalloproteinase-1, -3, -8, and -13 mRNA expression in bovine nasal cartilage stimulated with oncostatin M in combination with interleukin 1{alpha} Ann Rheum Dis, March 1, 2001; 60(3): 254 - 261. [Abstract] [Full Text] [PDF]

				G. Zhao, M.-C. Monier-Faugere, M. C. Langub, Z. Geng, T. Nakayama, J. W. Pike, S. D. Chernausek, C. J. Rosen, L.-R. Donahue, H. H. Malluche, et al. Targeted Overexpression of Insulin-Like Growth Factor I to Osteoblasts of Transgenic Mice: Increased Trabecular Bone Volume without Increased Osteoblast Proliferation Endocrinology, July 1, 2000; 141(7): 2674 - 2682. [Abstract] [Full Text] [PDF]

				R. C. Pereira, V. Jorgetti, and E. Canalis Triiodothyronine induces collagenase-3 and gelatinase B expression in murine osteoblasts Am J Physiol Endocrinol Metab, September 1, 1999; 277(3): E496 - E504. [Abstract] [Full Text] [PDF]

				S. Mora, P. Pitukcheewanont, J. C. Nelson, and V. Gilsanz Serum Levels of Insulin-Like Growth Factor I and the Density, Volume, and Cross-Sectional Area of Cortical Bone in Children J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2780 - 2783. [Abstract] [Full Text]

				J. S. Toung, R. C. Ogle, R. F. Morgan, and W. H. Lindsey Insulinlike Growth Factor 1- and 2-Augmented Collagen Gel Repair of Facial Osseous Defects Arch Otolaryngol Head Neck Surg, April 1, 1999; 125(4): 451 - 455. [Abstract] [Full Text] [PDF]

				E. Gazzerro, S. Rydziel, and E. Canalis Skeletal Bone Morphogenetic Proteins Suppress the Expression of Collagenase-3 by Rat Osteoblasts Endocrinology, February 1, 1999; 140(2): 562 - 567. [Abstract] [Full Text]

				T. Kawane and N. Horiuchi Insulin-Like Growth Factor I Suppresses Parathyroid Hormone (PTH)/PTH-Related Protein Receptor Expression via a Mitogen-Activated Protein Kinase Pathway in UMR-106 Osteoblast-Like Cells Endocrinology, February 1, 1999; 140(2): 871 - 879. [Abstract] [Full Text]

				V. Gangji, S. Rydziel, B. Gabbitas, and E. Canalis Insulin-Like Growth Factor II Promoter Expression in Cultured Rodent Osteoblasts and Adult Rat Bone Endocrinology, May 1, 1998; 139(5): 2287 - 2292. [Abstract] [Full Text] [PDF]

				N. Franchimont, S. Rydziel, A. M. Delany, and E. Canalis Interleukin-6 and Its Soluble Receptor Cause a Marked Induction of Collagenase 3 Expression in Rat Osteoblast Cultures J. Biol. Chem., May 2, 1997; 272(18): 12144 - 12150. [Abstract] [Full Text] [PDF]

				S. Varghese and E. Canalis Regulation of Collagenase-3 by Bone Morphogenetic Protein-2 in Bone Cell Cultures Endocrinology, March 1, 1997; 138(3): 1035 - 1040. [Abstract] [Full Text] [PDF]

				J. Hess, D. Porte, C. Munz, and P. Angel AP-1 and Cbfa/Runt Physically Interact and Regulate Parathyroid Hormone-dependent MMP13 Expression in Osteoblasts through a New Osteoblast-specific Element 2/AP-1 Composite Element J. Biol. Chem., June 1, 2001; 276(23): 20029 - 20038. [Abstract] [Full Text] [PDF]