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This version published online on August 7, 2003
Endocrinology, doi:10.1210/en.2003-0745
A more recent version of this article appeared on November 1, 2003
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Submitted on June 13, 2003
Accepted on July 30, 2003

LACK OF IGF-1 EXAGGERATES THE EFFECT OF CALCIUM DEFICIENCY ON BONE ACCRETION IN MICE

Yuji Kasukawa1, David J. Baylink1, Jon E. Wergedal1, Yousef Amaar1, Apurva K. Srivastava1, Rongqing Guo1, and Subburaman Mohan1*

1 Musculoskeletal Disease Center, JL Pettis VA Medical Center, Loma Linda, CA 92357, USA; Department of Medicine, Loma Linda University, Loma Linda, CA 92350; Department of Biochemistry, Loma Linda University, Loma Linda, CA 92350; Department of Physiology, Loma Linda University, Loma Linda, CA 92350

* To whom correspondence should be addressed. E-mail: mohans{at}lom.med.va.gov.

Recent studies provide evidence that growth hormone (GH)/IGF-I axis plays a critical role in the regulation of bone accretion that occurs during puberty and that the peak BMD is dependent on the amount of dietary calcium intake during the active growth phases. To evaluate if IGF-I deficiency exaggerates the effect of calcium (Ca) deficiency on bone accretion during active growth phases, IGF-I KO and WT mice were fed with low Ca (0.01%) or normal Ca (0.6%) for 2 weeks during pubertal growth phase and labeled with tetracycline. Low Ca diet caused significant decreases in endosteal bone formation parameters and a much greater increase in the resorbing surface of both the endosteum and periosteum of the tibia of IGF-I KO mice compared with WT mice. Accordingly, femur BMD measured by DEXA or pQCT increased significantly in IGF-I WT mice fed with low Ca but not in IGF-I KO mice. IGF-I deficient mice fed with normal calcium diet showed elevated PTH levels, decreased serum 1,25 D and serum Ca levels at baseline. Serum Ca changes due to Ca deficiency were greater in IGF-I KO mice compared with WT mice. PTH levels were 7-fold higher in IGF-I KO mice fed with normal Ca compared with WT mice, which was further elevated in mice fed with low Ca diet. Treatment of IGF-I deficient lit/lit mice with GH decreased the serum PTH level by 70% (P < 0.01). Based on these and past findings, we conclude that 1) IGF-I deficiency exaggerates the negative effects of Ca deficiency on bone accretion; and 2) IGF-I deficiency may lead to 1,25 D deficiency and elevated PTH levels even under normal calcium diet.
Key words: low calcium diet • Insulin-like growth factor-I • PTH • secondary hyperparathyrodism • vitamin D • IGF-I knockout mice • bone




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