Document Detail

Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation.
MedLine Citation:
PMID:  23321671     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-16
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  666-81     Citation Subset:  AIM; IM    
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
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MeSH Terms
Bone Marrow Cells / cytology,  metabolism
Bone Resorption / enzymology,  pathology,  prevention & control
Cathepsin K / antagonists & inhibitors,  deficiency*,  genetics
Cell Differentiation
Feedback, Physiological
Lysophospholipids / metabolism*
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
Reg. No./Substance:
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 K; EC protein, mouse

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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