Cathepsin K-deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression
Cathepsin K-deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression
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DOI：
10.1172/jci122936
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发表时间：
2019-08-01
影响因子：
15.9
通讯作者：
Baron, Roland
中科院分区：
文献类型：
--
作者：
Lotinun, Sutada;Ishihara, Yoshihito;Baron, Roland
哺乳诱导骨丢失以在乳汁中提供足够的钙，这一过程涉及骨细胞骨吸收，但也涉及骨细胞和骨陷窝周围吸收。骨细胞导致骨丢失的确切机制仍然难以捉摸。骨细胞表达破骨细胞骨吸收所需的基因，包括组织蛋白酶K（Ctsk），哺乳提高了它们的表达。我们发现，骨细胞中的Ctsk缺失防止了哺乳期间骨细胞腔隙面积的增加，以及哺乳增加破骨细胞数量和减少骨小梁体积、皮质厚度和机械性能的影响。此外，我们发现骨细胞中的Ctsk缺失增加了骨甲状旁腺素相关肽（PTHrP），并防止了哺乳引起的血清甲状旁腺素（PTH）的降低，但增加了血清1，25-二羟基维生素D [1，25（OH）（2）D]。这些变化的最终结果是将血清和乳汁中的钙水平维持在正常范围内，确保后代骨骼发育正常。我们的研究证实了哺乳期生理状态下骨细胞骨腔周围重塑的基本作用，并提供了遗传学证据，证明骨细胞来源的Ctsk不仅有助于骨细胞骨腔周围重塑，而且还调节PTH、PTHrP、1，25（OH）（2）D、破骨细胞生成和骨质丢失，以响应与哺乳期相关的高钙需求。
Lactation induces bone loss to provide sufficient calcium in the milk, a process that involves osteoclastic bone resorption but also osteocytes and perilacunar resorption. The exact mechanisms by which osteocytes contribute to bone loss remain elusive. Osteocytes express genes required in osteoclasts for bone resorption, including cathepsin K (Ctsk), and lactation elevates their expression. We show that Ctsk deletion in osteocytes prevented the increase in osteocyte lacunar area seen during lactation, as well as the effects of lactation to increase osteoclast numbers and decrease trabecular bone volume, cortical thickness, and mechanical properties. In addition, we show that Ctsk deletion in osteocytes increased bone parathyroid hormone-related peptide (PTHrP) and prevented the decrease in serum parathyroid hormone (PTH) induced by lactation, but amplified the increase in serum 1,25-dyhydroxyvitamin D [1,25(OH)(2)D]. The net result of these changes is to maintain serum and milk calcium levels in the normal range, ensuring normal offspring skeletal development. Our studies confirm the fundamental role of osteocytic perilacunar remodeling in physiological states of lactation and provide genetic evidence that osteocyte-derived Ctsk contributes not only to osteocyte perilacunar remodeling, but also to the regulation of PTH, PTHrP, 1,25(OH)(2)D, osteoclastogenesis, and bone loss in response to the high calcium demand associated with lactation.