This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Govoni, K. E. Articles by Mohan, S. Search for Related Content PubMed PubMed Citation Articles by Govoni, K. E. Articles by Mohan, S.

Conditional Deletion of Insulin-Like Growth Factor-I in Collagen Type 12-Expressing Cells Results in Postnatal Lethality and a Dramatic Reduction in Bone Accretion

Musculoskeletal Disease Center (K.E.G., J.E.W., S.M.), Jerry L. Pettis Veterans Affairs Medical Center, Loma Linda, California 92357; Department of Medicine (J.E.W., D.J.B., S.M.), Loma Linda University, Loma Linda, California 92354; and German Cancer Research Center (L.F., P.A.), D-69120 Heidelberg, Germany

Address all correspondence and requests for reprints to: Subburaman Mohan, Ph.D., Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial Veterans Affairs Medical Center, 11201 Benton Street, Loma Linda, California 92357. E-mail: subburaman.mohan{at}va.gov.

IGF-I acts through endocrine and local, autocrine/paracrine routes. Disruption of both endocrine and local IGF-I action leads to neonatal lethality and impaired growth in various tissues including bone; however, the severity of growth and skeletal phenotype caused by disruption of endocrine IGF-I action is far less than with total IGF-I disruption. Based on these data and the fact that bone cells express IGF-I in high abundance, we and others predicted that locally produced IGF-I is also critical in regulating growth and bone accretion. To determine the role of local IGF-I, type 12 collagen-Cre mice were crossed with IGF-I loxP mice to generate Cre+ (conditional mutant) and Cre– (control) loxP homozygous mice. Surprisingly, approximately 40–50% of the conditional mutants died at birth, which is similar to total IGF-I disruption, but not observed in mice lacking circulating IGF-I. Expression of IGF-I in bone and muscle but not liver and brain was significantly decreased in the conditional mutant. Accordingly, circulating levels of serum IGF-I were also not affected. Disruption of local IGF-I dramatically reduced body weight 28–37%, femur areal bone mineral density 10–25%, and femur bone size 18–24% in growing mice. In addition, mineralization was reduced as early as during embryonic development. Consistently, histomorphometric analysis determined impaired osteoblast function as demonstrated by reduced mineral apposition rate (14–30%) and bone formation rate (35–57%). In conclusion, both local and endocrine IGF-I actions are involved in regulating growth of various tissues including bone, but they act via different mechanisms.

This article has been cited by other articles:

				C. Ohlsson, S. Mohan, K. Sjogren, A. Tivesten, J. Isgaard, O. Isaksson, J.-O. Jansson, and J. Svensson The Role of Liver-Derived Insulin-Like Growth Factor-I Endocr. Rev., August 1, 2009; 30(5): 494 - 535. [Abstract] [Full Text] [PDF]

				I. Ueki, S. L. Giesy, K. J. Harvatine, J. W. Kim, and Y. R. Boisclair The Acid-Labile Subunit Is Required for Full Effects of Exogenous Growth Hormone on Growth and Carbohydrate Metabolism Endocrinology, July 1, 2009; 150(7): 3145 - 3152. [Abstract] [Full Text] [PDF]

				E. Stratikopoulos, M. Szabolcs, I. Dragatsis, A. Klinakis, and A. Efstratiadis The hormonal action of IGF1 in postnatal mouse growth PNAS, December 9, 2008; 105(49): 19378 - 19383. [Abstract] [Full Text] [PDF]

				K. E. Govoni, J. E. Wergedal, R. B. Chadwick, A. K. Srivastava, and S. Mohan Prepubertal OVX increases IGF-I expression and bone accretion in C57BL/6J mice Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1172 - E1180. [Abstract] [Full Text] [PDF]