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Hereditary Resistance to 1,25-Dihydroxyvitamin D: Defective Function of Receptors for 1,25-Dihydroxy vitamin D in Cells Cultured from Bone^*

Metabolic Diseases Branch, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases Bethesda, Maryland 20205
Beilinson Medical Center Tel Aviv University Medical School Tel Aviv, Israel
Endocrinology Branch, Department of Medicine, National Naval Medical Center and Uniformed Services University of the Health Sciences Bethesda, Maryland 20814
Department of Orthopedics, School of Medicine, University of Southern California Los Angeles, California 90007
Department of Pediatrics, Albert Einstein College of Medicine, Montefiore Hospital and Medical Center Bronx, New York 10467

Address correspondence and requests for reprints to: Dr. S. J. Marx, National Institutes of Health, Building 10, Room 9C-101, Bethesda, Maryland 20205.

The syndrome of rickets, alopecia, hypocalcemia, and high circulating levels of 1,25-dihydroxyvitamin D (1,25-(OH)₂D) apparently is caused by resistance of target tissues to 1,25-(OH)₂D. To evaluate this, we cultured cells from explants of long bone of one patient with this syndrome and from a control without any preexisting disorder of mineral metabolism.

The cultured cells showed morphological features of fibroblasts but contained alkaline phosphatase activity without detectable acid phosphatase activity, indicating an osteoblastic origin for some or all of the cultured cells. Receptors for 1,25-(OH)₂D were assessed by three methods: high affinity uptake of hormone in nuclei of dispersed cells, high affinity binding in hypertonic extracts (herein termed cytosol) from cells, and sedimentation velocity of bound [³H]1,25-(OH)₂D₃ in extracts of cell nuclei. With cells cultured from bone of the normal control, receptors for 1,25-(OH)₂D exhibited properties indistinguishable from those found with cultured skin fibroblasts. With cells cultured from bone of the patient with resistance to 1,25-(OH)₂D, high affinity uptake of 1,25-(OH)₂D into nuclei was unmeasurable, but high affinity binding of hormone with cytosol was normal; these abnormal findings also were indistinguishable from abnormal findings obtained with fibroblasts cultured from skin of that patient.

In conclusion: 1) Cells cultured from explants of human bone showed morphological features of fibroblasts but retained a marker enzyme characteristic of osteoblasts. Significant admixture of osteoblast-like cells with fibroblasts was possible. 2) Cells cultured from bone of a patient with familial resistance to 1,25-(OH)₂D exhibit a defect in vitamin D metabolism, indistinguishable from the defect observed with cells cultured from skin of the same patient.

^* This work was supported in part by NIH Grant ES-01060-08 and by CIC Project 81-06-1516 from the Bureau of Medicine and Surgery, Navy Department, Washington, D. C. The opinions expressed herein are those of the authors and are not to be construed as reflecting the views of the Navy Department, of the Naval Service at large, or of the Department of Defense.

Received February 18, 1983.

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