Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene
Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene
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DOI：
10.1172/jci200214218
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发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
Gagel, RF
中科院分区：
文献类型：
--
作者：
Hoff, AO;Catala-Lehnen, P;Gagel, RF
降钙素（CT）是一种已知的骨吸收抑制剂。降钙素基因相关肽-α。由CT/CGRP基因的替代RNA加工产生的CGRP α（CGRPalpha）在骨中没有明确的作用。为了更好地理解CT/CGRP基因的生理作用，我们创建了一种小鼠，其中CT和CGRP α的编码序列通过同源重组被删除。CT/CGRP（-/-）敲除（KO）小鼠生育正常，出生时没有可识别的发育缺陷，并且具有正常的基线钙相关化学值。然而，KO动物对外源性人甲状旁腺激素的反应性更强，表现为血清钙浓度和尿脱氧吡啶啉交联的增加更大，CT逆转了这种效应，并通过骨吸收的增加比对照组更大来介导。令人惊讶的是，KO小鼠在1月龄和3月龄时具有显著更大的骨小梁体积和1.5至2倍的骨形成增加。这种作用似乎是通过增加骨形成介导的。此外，KO小鼠在卵巢切除术后保持骨量，而野生型小鼠在2个月内损失约三分之一的骨量。这些研究结果认为CT/CGRP基因产物的双重作用：预防高钙状态下的骨吸收和骨形成的调节作用。
Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-alpha. (CGRPalpha), produced by alternative RNA processing of the CT/CGRP gene, has no clearly defined role in bone. To better understand the physiologic role of the CT/CGRP gene we created a mouse in which the coding sequences for both CT and CGRPalpha were deleted by homologous recombination. The CT/CGRP(-/-) knockout (KO) mice procreated normally, there were no identifiable developmental defects at birth, and they had normal baseline calcium-related chemistry values. However, KO animals were more responsive to exogenous human parathyroid hormone as evidenced by a greater increase of the serum calcium concentration and urine deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater increase in bone resorption than in controls. Surprisingly, KO mice have significantly greater trabecular bone volume and a 1.5- to 2-fold increase in bone formation at 1 and 3 months of age. This effect appears to be mediated by increased bone formation. In addition, KO mice maintain bone mass following ovariectomy, whereas wild-type mice lose approximately one-third of their bone mass over 2 months. These findings argue for dual roles for CT/CGRP gene products: prevention of bone resorption in hypercalcemic states and a regulatory role in bone formation.