Building up and breaking down


Mutations in the human cathepsin K (CTSK) cause pycnodysostosis, an autosomal recessive disease characterized by short stature and elevated bone density (osteopetrosis). In mice, global deletion of Ctsk results in decreased bone resorption and osteopetrosis, but also enhances the rate of bone formation. To determine the role of CTSK in bone formation, Sutada Lotinun and colleagues generated osteoclast- and osteoblast-specific Ctsk knockout mice. The accompanying confocal microscopy images show osteoclasts stained with antibodies against the secretory lyosomal marker synaptotagmin 7 (green), actin (phalloidin/red), and nuclei (stained with To-Pro/blue). Lotinun and colleagues identified molecular mechanisms explaining how loss of CTSK enhances bone formation. CTSK inhibitors are currently being assessed in human clinical trials for the treatment of osteoporosis.

Published January 16, 2013, by Jillian Hurst

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Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation
Sutada Lotinun, … , William C. Horne, Roland Baron
Sutada Lotinun, … , William C. Horne, Roland Baron
Published January 16, 2013
Citation Information: J Clin Invest. 2013;123(2):666-681. https://doi.org/10.1172/JCI64840.
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Research Article Bone biology

Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation

Abstract

Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-1-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P1,3 receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P.

Authors

Sutada Lotinun, Riku Kiviranta, Takuma Matsubara, Jorge A. Alzate, Lynn Neff, Anja Lüth, Ilpo Koskivirta, Burkhard Kleuser, Jean Vacher, Eero Vuorio, William C. Horne, Roland Baron

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