In Vivo Inhibition of Osteoblastic Metalloproteinases Leads to Increased Trabecular Bone Mass

Abstract

Mice specifically overexpressing TIMP-1 in osteoblasts have been generated to investigate the role of MMPs in bone in vivo. These mice displayed increased trabecular bone volume and decreased bone turnover. This model provides evidence of the role played by the MMPs in bone remodeling and balance.Introduction: Although it has been suggested that the matrix metalloproteinases (MMPs) may play a role in initiating the bone resorption process in vitro, there is no evidence that they play any role in in vivo bone maintenance. Materials and Methods:We used an artificial promoter specifically driving cells of the osteoblastic lineage to overexpress the tissue inhibitor of MMPs (TIMP-1) cDNA in mice. Densitometric analysis, using DXA and pQCT, and static and dynamic histomorphometry were used to evaluate the bone phenotype both in male and female transgenic mice. We evaluated osteoblastic differentiation using a primary osteoblast culture and osteoclast activity using an ex vivo organ culture. Results and Conclusion:We showed that at 1 and 2.5 months of age, only the female mice exhibited a bone phenotype. These mice displayed specific increases in the BMD and bone volume of trabecular bone. This increase was accompanied by decreased trabecular separation, suggesting a decrease in bone resorption. Using an ex vivo resorption assay, we demonstrated that parathyroid hormone (PTH)-stimulated bone resorption was reduced in these mice. Evaluation of the bone histomorphometric dynamic parameters showed that the mineralizing surfaces and bone formation rate were both reduced. There was no change in the mineralization lag time or number of osteocyte lacunae. Using primary osteoblast culture and molecular analysis, we showed that the differentiation and function of osteoblasts from transgenic mice were normal, but that the ex vivo formation of mineralized nodules was delayed. This model is the first to show that in vivo MMPs play a role in bone remodeling and bone balance. Moreover, our data suggest that MMP activity could be involved in the hormonal regulation of bone resorption by osteoblasts.

Dlx5, a Positive Regulator of Osteoblastogenesis, is Essential for Osteoblast-Osteoclast Coupling

“…21 Histomorphometric parameters were measured in accordance to the ASBMR nomenclature 22 on 5 m sections using a Nikon microscope interfaced with the software package Microvision Instruments (Evry, France). Sections were stained with aniline blue.…”

Stretch-induced modulation of matrix metalloproteinases in mineralizing osteoblasts via extracellular signal-regulated kinase-1/2

“…MMPs and TIMPs are known to be involved in various physiological processes both in normal bone remodeling and under pathological conditions such as osteoporosis and rheumatoid arthritis. [12][13][14] Direct regulation of MMPs or TIMPs by mechanical loading would provide an interesting means by which mechanical loading can regulate the spatial control of bone metabolism. Yet only very limited data are available on the interaction between mechanical loading and MMPs or TIMPs in osteoblasts.…”

Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation

“…Mice specifically overexpressing TIMP-1 in osteoblasts have been generated to investigate the role of MMPs in bone in vivo (24). These mice displayed increased trabecular bone volume and decreased bone turnover, providing evidence of the role played by the MMPs in bone remodeling and balance (24).…”