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J. Biol. Chem., Vol. 279, Issue 50, 52406-52413, December 10, 2004

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Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k^*

Wei Zheng, Yixia Xie, Gang Li¶, Juan Kong, Jian Q. Feng, and Yan Chun Li||

From the Department of Medicine, University of Chicago, Chicago, Illinois 60637, the Department of Oral Biology, School of Dentistry, University of Missouri, Kansas City, Missouri 64108, and the ^¶Department of Trauma and Orthopaedic Surgery, School of Medicine, Queen's University Belfast, Musgrave Park Hospital, Belfast BT9 7JB, Northern Ireland United Kingdom

Calbindin (CaBP)-D28k and CaBP-D9k are cytosolic vitamin D-dependent calcium-binding proteins long thought to play an important role in transepithelial calcium transport. However, recent genetic studies suggest that CaBP-D28k is not essential for calcium metabolism. Genetic ablation of this gene in mice leads to no calcemic abnormalities. Genetic inactivation of the vitamin D receptor (VDR) gene leads to hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia, accompanied by 90% reduction in renal CaBP-D9k expression but little change in CaBP-D28k. To address whether the role of CaBP-D28k in calcium homeostasis is compensated by CaBP-D9k, we generated VDR/CaBP-D28k double knockout (KO) mice, which expressed no CaBP-D28k and only 10% of CaBP-D9k in the kidney. On a regular diet, the double KO mice were more growth-retarded and 42% smaller in body weight than VDRKO mice and died prematurely at 2.5–3 months of age. Compared with VDRKO mice, the double KO mice had higher urinary calcium excretion and developed more severe secondary hyperparathyroidism and rachitic skeletal phenotype, which were manifested by larger parathyroid glands, higher serum parathyroid hormone levels, much lower bone mineral density, and more distorted growth plate with more osteoid formation in the trabecular region. On high calcium, high lactose diet, blood-ionized calcium levels were normalized in both VDRKO and the double KO mice; however, in contrast to VDRKO mice, the skeletal abnormalities were not completely corrected in the double KO mice. These results directly demonstrate that CaBP-D28k plays a critical role in maintaining calcium homeostasis and skeletal mineralization and suggest that its calcemic role can be mostly compensated by CaBP-D9k.

Received for publication, May 19, 2004 , and in revised form, September 9, 2004.

^* This work was supported by National Institutes of Health Grants DK59327 (to Y. C. L.) and AR51587 (to J. Q. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Medicine, University of Chicago, MC 4076, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-2477; Fax: 773-702-5790; E-mail: cyan{at}medicine.bsd.uchicago.edu.

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