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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.

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