| Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. | |
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MedLine Citation:
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PMID: 23321671 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2013-01-16 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 123 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2013 Feb |
Date Detail:
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Created Date: 2013-04-19 Completed Date: 2013-05-13 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 666-81 Citation Subset: AIM; IM |
Affiliation:
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Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bone Marrow Cells / cytology, metabolism Bone Resorption / enzymology, pathology, prevention & control Cathepsin K / antagonists & inhibitors, deficiency*, genetics Cell Differentiation Feedback, Physiological Female Lysophospholipids / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Models, Biological Osteoblasts / cytology, enzymology Osteoclasts / cytology, enzymology* Osteogenesis / genetics, physiology* Osteoprotegerin / metabolism RANK Ligand / metabolism Sphingosine / analogs & derivatives*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Lysophospholipids; 0/Osteoprotegerin; 0/RANK Ligand; 0/Tnfrsf11b protein, mouse; 0/Tnfsf11 protein, mouse; 123-78-4/Sphingosine; 26993-30-6/sphingosine 1-phosphate; EC 3.4.22.38/Cathepsin K; EC 3.4.22.38/Ctsk protein, mouse |
| Comments/Corrections | |
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