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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 4

Osteocyte-specific deletion of Ctsk prevents bone loss in lactating mice.

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Osteocyte-specific deletion of Ctsk prevents bone loss in lactating mice...
Histomorphometric analysis of distal femurs from virgin and lactating Ctskfl/fl (black dots and squares, respectively) and Ctskocy (red dots and squares, respectively) mice. Results represent the mean ± SEM. †P < 0.05 versus virgin Ctskfl/fl mice; ‡P < 0.05 versus virgin Ctskocy mice; and #P < 0.05 versus lactating Ctskfl/fl mice (n = 6–9 per group). A 2-way ANOVA followed by Fisher’s PLSD test was used to determine statistical significance. O.Th, osteoid thickness.
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