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Endocrinology Vol. 141, No. 7 2674-2682
Copyright © 2000 by The Endocrine Society

ARTICLES

Targeted Overexpression of Insulin-Like Growth Factor I to Osteoblasts of Transgenic Mice: Increased Trabecular Bone Volume without Increased Osteoblast Proliferation1

Guisheng Zhao, Marie-Claude Monier-Faugere, Moises Chris Langub, Zhaopo Geng, Toshiyuki Nakayama, J. Wesley Pike, Steven D. Chernausek, Clifford J. Rosen, Leah-Rae Donahue, Hartmut H. Malluche, James A. Fagin and Thomas L. Clemens

Division of Endocrinology (G.Z., T.N., J.W.P., J.A.F., T.L.C.), Departments of Medicine and Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Research Service (T.L.C.), Veterans Administration Medical Center, Cincinnati, Ohio 45220; Division of Nephrology, Bone and Mineral Metabolism (M.-C.M.-F., M.C.L., Z.G., H.H.M.), University of Kentucky School of Medicine, Lexington, Kentucky 40536; Division of Endocrinology (S.D.C.), Children’s Hospital, Cincinnati, Ohio 45229; Maine Center for Osteoporosis Research and Education (C.R., L.-R.D.), St. Joseph Hospital, Bangor, Maine 04401

Address all correspondence and requests for reprints to: Thomas L. Clemens, Ph.D., Division of Endocrinology, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, Ohio 45267. E-mail: Clementl{at}uc.edu

Insulin-like growth factor I (IGF-I) is an important growth factor for bone, yet the mechanisms that mediate its anabolic activity in the skeleton are poorly understood. To examine the effects of locally produced IGF-I in bone in vivo, we targeted expression IGF-I to osteoblasts of transgenic mice using a human osteocalcin promoter. The IGF-I transgene was expressed in bone osteoblasts in OC-IGF-I transgenic mice at high levels in the absence of any change in serum IGF-I levels, or of total body growth. Bone formation rate at the distal femur in 3-week-old OC-IGF-I transgenic mice was approximately twice that of controls. By 6 weeks, bone mineral density as measured by dual energy x-ray, and quantitative computed tomography was significantly greater in OC-IGF-I transgenic mice compared with controls. Histomorphometric measurements revealed a marked (30%) increase femoral cancellous bone volume in the OC-IGF-I transgenic mice, but no change in the total number of osteoblasts or osteoclasts. Transgenic mice also demonstrated an increase in the osteocyte lacunea occupancy, suggesting that IGF-I may extend the osteocyte life span. We conclude that IGF-I produced locally in bone osteoblasts exerts its anabolic effect primarily by increasing the activity of resident osteoblasts.




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