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Cathepsin K–deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression
Sutada Lotinun, … , Francesca Gori, Roland Baron
Sutada Lotinun, … , Francesca Gori, Roland Baron
Published May 21, 2019
Citation Information: J Clin Invest. 2019;129(8):3058-3071. https://doi.org/10.1172/JCI122936.
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Research Article Bone Biology Endocrinology

Cathepsin K–deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression

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Abstract

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)2D]. 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)2D, osteoclastogenesis, and bone loss in response to the high calcium demand associated with lactation.

Authors

Sutada Lotinun, Yoshihito Ishihara, Kenichi Nagano, Riku Kiviranta, Vincent T. Carpentier, Lynn Neff, Virginia Parkman, Noriko Ide, Dorothy Hu, Pamela Dann, Daniel Brooks, Mary L. Bouxsein, John Wysolmerski, Francesca Gori, Roland Baron

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Figure 1

Normal skeletal homeostasis in mice with osteocyte-specific deletion of Ctsk at steady state.

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Normal skeletal homeostasis in mice with osteocyte-specific deletion of ...
(A) Representative images of Ctsk immunostaining in osteocytes from Ctskfl/fl and Ctskocy mice (n = 3 per group). Scale bars: 20 μm. (B) qRT-PCR analysis of Ctsk expression in BM-depleted distal femur from 12-week-old Ctskfl/fl (black dots) and Ctskocy (red dots) mice. (n = 5 per group). *P < 0.05, by Student’s t test versus Ctskfl/fl mice. Data are expressed as the mean ± SEM. (C) Representative images of Ctsk immunostaining in osteoclasts from Ctskfl/fl and Ctskocy mice (n = 3). Scale bars: 5 μm. (D) qRT-PCR analysis of relative Ctsk expression in osteoclasts. Ctskfl/fl (black dots) and Ctskocy (red dots) mice (n = 3 per group). Data are expressed as the mean ± SEM. (E) Representative μCT images of the cortical area and the trabecular microarchitecture of tibiae from 12-week-old female Ctskfl/fl and Ctskocy mice (n = 6 per group). Scale bars: 100 μm.
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