MMP14 and Regulation of the Hypertrophic Chondrocyte to Osteoblast Lineage

Abstract

During endochondral ossification, cartilage template is degraded by matrix metalloproteinases(MMPs) and replaced by bone. Currently, hypertrophic chondrocytes(HCs) undergo lineage extension and contribute to osteoblasts in trabeculae. However, the role of MMPs in regulating the lineage transition of HCs to osteoblast is unknown. MMP14(MT1-MMP), encoded by Mmp14, is a membrane-tethered matrix metalloproteinase which is highly expressed by cells at the chondro-osseous junction where lineage extension of HCs occurs. Here we show that by following the fate of HCs using Col10a1-Cre and Rosa26 reporters, complete inactivation of MMP14 in vivo results in loss of trabecular bone and accumulation of HC-derived cells at the chondro-osseous junction. In situ hybridization of osteogenic markers such as Col1a1, Mmp13 and Opn are decreased in MMP14 mutants. Live cell imaging of endochondral bone explants suggests HC-descendents undergo active migration at the chondro-osseous junction. Conversely, conditional ablation of MMP14 in HC descendent cells causes increased trabecular bone and decreased apoptosis of HCs at the chondro-osseous junction. We found that MMP14 interacts and cleaves parathyroid hormone 1 receptor(PTH1R) which governs the development of chondrocytes, metabolism of osteoblasts as well as fate decision of HCs. Haloinsuffuciency of pth1r partially rescues postnatal endochondral ossification in Mmp14-/- mice. Our work unravels an important function of MMP14 in lineage progression of hypertrophic chondrocytes.