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

Abstract

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.

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

“…Indeed, TIMP-1 has been shown to inhibit bone resorption, decrease bone turnover, and reduce bone loss in a mouse model when overexpressed by osteoblasts. (39)(40)(41) Thus, the cytokine profile supports the idea that Sc65 is a negative regulator of osteoclastogenesis. These data also suggest that further studies of the role of Sc65 are warranted and are ongoing in additional cohorts of mice.…”

“…Similarly, the downregulation of TIMP‐1, an MMP‐9 inhibitor, would also support a pro‐osteolytic resorption environment in vivo. Indeed, TIMP‐1 has been shown to inhibit bone resorption, decrease bone turnover, and reduce bone loss in a mouse model when overexpressed by osteoblasts . Thus, the cytokine profile supports the idea that Sc65 is a negative regulator of osteoclastogenesis.…”

Inhibition of bone resorption blunts osteoarthritis in mice with high bone remodelling

“…We demonstrated previously that Mnx-induced OA was prevented by systemic administration of OPG, a potent inhibitor of bone resorption 18. Indeed, osteoblast precursors from Runx2 transgenic mice have an enhanced expression and production of RANKL 22 35. Therefore, blocking bone remodelling by pamidronate may have decreased the secretion of RANKL by bone cells and thereby prevented the degradation of cartilage.…”

Mechanical forces‐induced human osteoblasts differentiation involves MMP‐2/MMP‐13/MT1‐MMP proteolytic cascade

“…differentiation [Marie, 2008], and MMP-13 expression [Jimenez et al, 1999], in mice leads to a dramatic bone loss [Schiltz et al, 2010]. Emerging data indicate that osteoblast differentiation is accompanied by MMP expression, which in turn, as a feedback mechanism, can regulate cell fate and differentiation [Manduca et al, 2009;Lu et al, 2010].…”