# MMP14 cleaves PTH1R in the chondrocyte derived osteoblast lineage, curbing signaling intensity for proper bone anabolism

Tsz Long Chu<sup>1,2</sup>, Peikai Chen<sup>1,3</sup>, Anna Xiaodan Yu<sup>1</sup>, Mingpeng Kong<sup>1</sup>, , Zhijia Tan<sup>1,3</sup>, Kwok Yeung Tsang<sup>1</sup>, Zhongjun Zhou<sup>1</sup> and Kathryn S.E. Cheah<sup>1*</sup>

<h3>Abstract</h3>
Bone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how PTH-signaling intensity in progenitors is controlled is unclear. Endochondral bone osteoblasts arise from perichondrium-derived osteoprogenitors and hypertrophic chondrocytes (HC). We found, via single-cell transcriptomics, HC descendent cells activate membrane-type 1 metalloproteinase 14 (MMP14) and the PTH pathway as they transition to osteoblasts in neonatal and adult mice. Unlike Mmp14 global knockouts, HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling and PTH signaling is enhanced in Mmp14ΔHC mutants. We found HC-derived osteoblasts contribute ~50% of osteogenesis promoted by treatment with PTH 1-34 and this response was amplified in Mmp14ΔHC. MMP14 control of PTH signaling likely applies also to both HC- and non- HC-derived osteoblasts because their transcriptomes are highly similar. Our study identifies a novel paradigm of MMP14 activity-mediated titration of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases. 

<h3>BioRxiv</h3>
https://www.biorxiv.org/content/10.1101/2022.08.17.504252v1

<h3>Software and Data Availability</h3>

The scRNA-seq raw data supporting this study were deposited on NCBI GEO with accession number GSE159544. The processed data was interactively hosted on https://www.sbms.hku.hk/kclab/mmp14-hcob and part of the scripts for analyzing this data were deposited on github: https://github.com/hkukclab/mmp14-hcob .