Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo

Shen, Yi, Winkler, Ingrid G., Barbier, Valerie, Sims, Natalie A., Hendy, Jean and Lévesque, Jean-Pierre (2010) Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. PLoS One, 5 9: e13086-1-e13086-13. doi:10.1371/journal.pone.0013086

Author Shen, Yi
Winkler, Ingrid G.
Barbier, Valerie
Sims, Natalie A.
Hendy, Jean
Lévesque, Jean-Pierre
Title Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2010-09-20
Year available 2010
Sub-type Article (original research)
DOI 10.1371/journal.pone.0013086
Open Access Status DOI
Volume 5
Issue 9
Start page e13086-1
End page e13086-13
Total pages 13
Place of publication San Francisco, CA, U.S.A.
Publisher Public Library of Science (PLoS)
Language eng
Formatted abstract
Background: Tissue inhibitor of metalloproteinases-3 (TIMP-3) inhibits matrix metalloproteinases and membrane-bound sheddases. TIMP-3 is associated with the extracellular matrix and is expressed in highly remodeling tissues. TIMP-3 function in the hematopoietic system is unknown.

Methodology/Principal Findings: We now report that TIMP-3 is highly expressed in the endosteal region of the bone marrow (BM), particularly by osteoblasts, endothelial and multipotent mesenchymal stromal cells which are all important cellular components of hematopoietic stem cell (HSC) niches, whereas its expression is very low in mature leukocytes and hematopoietic stem and progenitor cells. A possible role of TIMP-3 as an important niche component was further suggested by its down-regulation during granulocyte colony-stimulating factor-induced mobilization. To further investigate TIMP-3 function, mouse HSC were retrovirally transduced with human TIMP-3 and transplanted into lethally irradiated recipients. TIMP-3 overexpression resulted in decreased frequency of B and T lymphocytes and increased frequency of myeloid cells in blood and BM, increased Lineage-negative Sca-1+KIT+ cell proliferation in vivo and in vitro and increased colony-forming cell trafficking to blood and spleen. Finally, over-expression of human TIMP-3 caused a late onset fatal osteosclerosis.

Conclusions/Significance: Our results suggest that TIMP-3 regulates HSC proliferation, differentiation and trafficking in vivo, as well as bone and bone turn-over, and that TIMP-3 is expressed by stromal cells forming HSC niches within the BM. Thus, TIMP-3 may be an important HSC niche component regulating both hematopoiesis and bone remodeling.
Copyright: © 2010 Shen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keyword Colony-stimulating factor
Stem-cell mobilization
Growth-promoting activity
Progenitor cells
Long bones
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 288701
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2011 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 20 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 30 times in Scopus Article | Citations
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Created: Sun, 26 Dec 2010, 10:02:49 EST