Hermey D C, Popoff S N
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Endocrinology. 1995 Oct;136(10):4558-64. doi: 10.1210/endo.136.10.7664677.
Osteopetrosis describes a heterogeneous group of metabolic bone disorders characterized by a generalized skeletal sclerosis. Because reduced bone resorption coexists with elevated plasma levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D] in several osteopetrotic animals and children, skeletal resistance to this hormone has been proposed. In some mutations, such as the osteopetrotic (op) rat, the inability of 1,25-(OH)2D to elicit a skeletal response has been demonstrated. It is not known whether this resistance is localized to the skeleton or involves all target tissues. This study examined vitamin D receptor (VDR) status in the intestine and kidney from op rats and their normal littermates from 2-8 weeks of age. Quantitation of unoccupied VDR levels by Scatchard analysis demonstrated a delayed pattern of VDR expression in the intestine of op rats compared with their normal littermates; unoccupied VDR levels were up-regulated in op mutants from 5-8 weeks. Western analysis of 6-week-old mutant and normal intestinal, chromatin-associated protein revealed that total VDR levels were consistently and significantly elevated in all of the mutants examined. In op kidney, VDR numbers did not change as a function of age and were significantly down-regulated from 2-6 weeks of age compared with age-matched normal littermates. VDR affinity was similar in age-matched mutant and normal rats in both the intestine and kidney. In summary, these data suggest that skeletal resistance to 1,25-(OH)2D in op mutants is not the result of a generalized receptor defect resulting in reduced numbers or affinity. Furthermore, the up-regulation of intestinal VDR observed in older (5- to 8-week-old) mutants may reflect a compensatory mechanism to help establish and maintain normal serum calcium and phosphorus levels.
骨硬化症描述了一组异质性的代谢性骨病，其特征为全身性骨骼硬化。在一些患骨硬化症的动物和儿童中，骨吸收减少与血浆1,25 - 二羟维生素D [1,25-(OH)₂D]水平升高并存，因此有人提出骨骼对这种激素存在抵抗。在一些突变体中，如骨硬化症（op）大鼠，已证实1,25-(OH)₂D无法引发骨骼反应。目前尚不清楚这种抵抗是局限于骨骼还是涉及所有靶组织。本研究检测了op大鼠及其正常同窝仔鼠在2至8周龄时肠道和肾脏中的维生素D受体（VDR）状态。通过Scatchard分析对未占据的VDR水平进行定量分析表明，与正常同窝仔鼠相比，op大鼠肠道中VDR表达模式延迟；在5至8周龄的op突变体中，未占据的VDR水平上调。对6周龄突变体和正常肠道的染色质相关蛋白进行Western分析显示，在所有检测的突变体中，总VDR水平持续且显著升高。在op大鼠肾脏中，VDR数量不随年龄变化，与年龄匹配的正常同窝仔鼠相比，在2至6周龄时显著下调。在年龄匹配的突变体和正常大鼠的肠道和肾脏中，VDR亲和力相似。总之，这些数据表明，op突变体中骨骼对1,25-(OH)₂D的抵抗不是由受体数量减少或亲和力降低导致的全身性受体缺陷所致。此外，在较大龄（5至8周龄）突变体中观察到的肠道VDR上调可能反映了一种补偿机制，有助于建立和维持正常的血清钙和磷水平。
