Inhibition of osteoblastic metalloproteinases in mice prevents bone loss induced by oestrogen deficiency

Schiltz, Corinne; Marty, Caroline; Vernejoul, Marie‐Christine de; Geoffroy, Valérie

doi:10.1002/jcb.21747

Cited by 26 publications

(20 citation statements)

References 58 publications

(71 reference statements)

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“…This finding was consistent with our previous studies indicating that the main effect of TIMP-1 over-expression is to reduce bone resorption. Indeed, we demonstrated that the increase in bone mass induced by TIMP-1 over-expression in osteoblasts in young growing females (Geoffroy et al, 2004), its amplifying effect on the anabolic treatment with PTH (Merciris et al, 2007a), and its prevention of the bone loss induced by ovariectomy (Schiltz et al, 2008) were all related to decreased bone resorption parameters and in vivo activity. We now present further evidence showing that the decrease in bone resorption is not only associated with a decrease in osteoclast activity, but rather remarkably, with a decrease in osteoclast differentiation both in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 93%

“…Osteoblastic MMPs are important in both normal and pathological remodeling of bone, and in the balance between bone formation and resorption (Liu et al, 1995;Varghese, 2006). Using mice over-expressing TIMP-1, we showed previously that PTH-induced bone resorption is reduced in vivo (Merciris et al, 2007a), and that the bone loss induced by E2 deficiency is markedly reduced due to decreased osteoclast differentiation and function (Schiltz et al, 2008).…”

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confidence: 97%

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Bone loss induced by Runx2 Over‐expression in mice is blunted by osteoblastic over‐expression of TIMP‐1

Schiltz

Prouillet

Marty

et al. 2009

Journal Cellular Physiology

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The Runx2 gene is essential for osteoblast differentiation and function. In vivo over-expression of Runx2 in osteoblasts increases bone resorption, and blocks terminal osteoblast differentiation. Several lines of evidence suggest that osteoblastic matrix metalloproteinases (MMPs) could contribute to the increased bone resorption observed in mice over-expressing Runx2 (Runx2 mice). The goal of our study was to use a transgenic approach to find out whether the inhibition of osteoblastic MMPs can reduce the bone loss induced by the over-expression of Runx2. We analyzed the effect of the in vivo over-expression of the TIMP-1 in osteoblasts on the severe osteopenic phenotype in Runx2 mice. Females with the different genotypes (WT, Runx2, TIMP-1 and TIMP-1/Runx2) were analyzed for bone density, architecture, osteoblastic and osteoclastic activity and gene expression using qPCR. TIMP-1 over-expression reduces the bone loss in adult Runx2 mice. The prevention of the bone loss in TIMP-1/Runx2 mice was due to a combination of reduced bone resorption and sustained bone formation. We present evidence that the ability of osteoblastic cells to induce osteoclastic differentiation is lower in TIMP-1/Runx2 mice than in Runx2 mice, probably due to a reduction in the expression of RANK-L and of the Runx2 transgene. Osteoblast primary cells from TIMP-1/Runx2 mice, but not from Runx2 mice, were able to differentiate into fully mature osteoblasts producing high osteocalcin levels. In conclusion, our findings suggest that osteoblastic MMPs can affect osteoblast differentiation. Our work also indicates that osteoblastic MMPs are partly responsible for the bone loss observed in Runx2 transgenic mice.

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 97%

Bone loss induced by Runx2 Over‐expression in mice is blunted by osteoblastic over‐expression of TIMP‐1

Schiltz

Prouillet

Marty

et al. 2009

Journal Cellular Physiology

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“…The inhibition of TIMP-1 expression in hMSCs significantly promoted cell growth and differentiation into adult cells of the osteogenic lineage, indicating that TIMP-1 is an endogenous attenuator of these processes. Previous reports have shown that TIMP-1 inhibits epithelial cell proliferation and osteoblastic differentiation (23,24) but stimulates differentiation in hematopoietic progenitor cells, B cells, and Burkitt lymphoma cells (25)(26)(27). However, none of these studies has provided information regarding the underlying molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

Egea

Zahler

Rieth

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

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Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a matrix metalloproteinase (MMP)-independent regulator of growth and apoptosis in various cell types. The receptors and signaling pathways that are involved in the growth factor activities of TIMP-1, however, remain controversial. RNA interference of TIMP-1 has revealed that endogenous TIMP-1 suppresses the proliferation, metabolic activity, and osteogenic differentiation capacity of human mesenchymal stem cells (hMSCs). The knockdown of TIMP-1 in hMSCs activated the Wnt/β-catenin signaling pathway as indicated by the increased stability and nuclear localization of β-catenin in TIMP-1-deficient hMSCs. Moreover, TIMP-1 knockdown cells exhibited enhanced β-catenin transcriptional activity, determined by Wnt/β-catenin target gene expression analysis and a luciferase-based β-cateninactivated reporter assay. An analysis of a mutant form of TIMP-1 that cannot inhibit MMP indicated that the effect of TIMP-1 on β-catenin signaling is MMP independent. Furthermore, the binding of CD63 to TIMP-1 on the surface of hMSCs is essential for the TIMP-1-mediated effects on Wnt/β-catenin signaling. An array analysis of microRNAs (miRNAs) and transfection studies with specific miRNA inhibitors and mimics showed that let-7f miRNA is crucial for the regulation of β-catenin activity and osteogenic differentiation by TIMP-1. Let-7f was up-regulated in TIMP-1-depleted hMSCs and demonstrably reduced axin 2, an antagonist of β-catenin stability. Our results demonstrate that TIMP-1 is a direct regulator of hMSC functions and reveal a regulatory network in which let-7f modulates Wnt/β-catenin activity.plasticity | osteogenesis | canonical Wnt signaling

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“…Furthermore, mice lacking MMP-13 are reported to have increased bone volume due to decreased osteoclast formation and function, but also demonstrate enhanced osteoblast function [56]; [57]. TIMP-1 and TIMP-2 inhibit bone resorption in vitro ; and in young mice, TIMP-1 over-expression reduces bone resorption resulting in increased bone mass [58]; [59]. Synthetic inhibitors of MMPs and TIMP-2 can also inhibit osteoclast migration to bone resorption site, thus decreasing bone remodeling [60].…”

Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Regulates Hematopoiesis and Bone Formation In Vivo

et al. 2010

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BackgroundTissue 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 FindingsWe 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/SignificanceOur 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.

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Inhibition of osteoblastic metalloproteinases in mice prevents bone loss induced by oestrogen deficiency

Cited by 26 publications

References 58 publications

Bone loss induced by Runx2 Over‐expression in mice is blunted by osteoblastic over‐expression of TIMP‐1

Bone loss induced by Runx2 Over‐expression in mice is blunted by osteoblastic over‐expression of TIMP‐1

Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Regulates Hematopoiesis and Bone Formation In Vivo

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