Genetic analysis of the role of MMP14 during endochondral ossification

Abstract

It is traditionally believed that chondrocytes and osteoblasts are two separate lineages of cells with hypertrophic chondrocytes (HCs) being the terminal stage of chondrocyte differentiation. Previously, Yang et.al has provided evidence that HCs can become osteoblasts in vivo (Yang, Tsang et al. 2014). However, the critical factors involved in driving this cross-lineage transition are unknown.

MMP14, also known as MT1-MMP, encoded by Mmp14, is highly expressed at the chondro-osseous junction where the transition from HCs to osteoblasts takes place. MMP14 null mice display osteopenia, dwarfism and growth plate abnormalities during bone development. We hypothesize that MMP14 may regulate the transition of HCs to osteoblasts. To test this hypothesis, we generated compound mutant mouse models that allow us to trace the fate of HCs in MMP14 deficient mice. Here we show that knockout of Mmp14 results in severe loss of trabecular bone, accumulation of HC-descendent cells at the chondro-osseous junction. To define the role of MMP14 in the HC to osteoblast transition we ablated MMP14 specifically in HCs and their descendents. In these mice the trabecular bone, expression of Col1a1, Mmp13 and Opn were increased.

Collectively, our results suggest loss of MMP14 promotes the transition of HCs to osteoblasts. The novel phenotype we found implies MMP14 plays a specialized role in HC-derived osteoblasts.