Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo.
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/PRINCIP...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2948005?pdf=render |
| _version_ | 1819158766248001536 |
|---|---|
| author | Yi Shen Ingrid G Winkler Valerie Barbier Natalie A Sims Jean Hendy Jean-Pierre Lévesque |
| author_facet | Yi Shen Ingrid G Winkler Valerie Barbier Natalie A Sims Jean Hendy Jean-Pierre Lévesque |
| author_sort | Yi Shen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T16:29:52Z |
| format | Article |
| id | doaj.art-be7bf38a0f814d859d196c825c37d460 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T16:29:52Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-be7bf38a0f814d859d196c825c37d4602022-12-21T18:20:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0159e100114810.1371/journal.pone.0013086Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo.Yi ShenIngrid G WinklerValerie BarbierNatalie A SimsJean HendyJean-Pierre LévesqueBACKGROUND: 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.http://europepmc.org/articles/PMC2948005?pdf=render |
| spellingShingle | Yi Shen Ingrid G Winkler Valerie Barbier Natalie A Sims Jean Hendy Jean-Pierre Lévesque Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. PLoS ONE |
| title | Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. |
| title_full | Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. |
| title_fullStr | Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. |
| title_full_unstemmed | Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. |
| title_short | Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. |
| title_sort | tissue inhibitor of metalloproteinase 3 timp 3 regulates hematopoiesis and bone formation in vivo |
| url | http://europepmc.org/articles/PMC2948005?pdf=render |
| work_keys_str_mv | AT yishen tissueinhibitorofmetalloproteinase3timp3regulateshematopoiesisandboneformationinvivo AT ingridgwinkler tissueinhibitorofmetalloproteinase3timp3regulateshematopoiesisandboneformationinvivo AT valeriebarbier tissueinhibitorofmetalloproteinase3timp3regulateshematopoiesisandboneformationinvivo AT natalieasims tissueinhibitorofmetalloproteinase3timp3regulateshematopoiesisandboneformationinvivo AT jeanhendy tissueinhibitorofmetalloproteinase3timp3regulateshematopoiesisandboneformationinvivo AT jeanpierrelevesque tissueinhibitorofmetalloproteinase3timp3regulateshematopoiesisandboneformationinvivo |