MMP14 cleaves PTH1R in the chondrocyte derived osteoblast lineage, curbing signaling intensity for proper bone anabolism
- University of Hong Kong, Hong Kong
- University of Hong Kong - Shenzhen Hospital, China
Abstract
Bone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how the 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, postnatal day 10 (p10) HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling, and consistent with the implied regulatory role, in Mmp14ΔHC mutants, PTH signaling is enhanced. 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 modulation of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases.
Data availability
Sequencing data have been deposited in GEO under accession codes:GSE159544GSE222203All data generated or analysed during this study are included in the manuscript and supporting file; source data files have been provided for Figure 1.
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hypertrophic chondrocytes and osteogenesis in P6 mouse tibiaNCBI Gene Expression Omnibus, GSE159544.
Article and author information
Author details
Kathryn Song Eng Cheah
Funding
Research Grants Council, University Grants Committee (AoE/M-04/04)
- Kathryn Song Eng Cheah
Research Grants Council, University Grants Committee (T12-708/12N)
- Kathryn Song Eng Cheah
Health and Medical Research Fund (07183766)
- Kathryn Song Eng Cheah
Jimmy & Emily Tang Professorship (nil)
- Kathryn Song Eng Cheah
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Di Chen, Chinese Academy of Sciences, China
Ethics
Animal experimentation: Animal care and experiments were in accordance with the protocols approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong. Protocol nos: 3981-1, 5295-20, 5527-20.
Version history
- Received: July 25, 2022
- Preprint posted: August 17, 2022 (view preprint)
- Accepted: March 8, 2023
- Accepted Manuscript published: March 9, 2023 (version 1)
- Version of Record published: March 23, 2023 (version 2)
Copyright
© 2023, Chu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MMP14 cleaves PTH1R in the chondrocyte derived osteoblast lineage, curbing signaling intensity for proper bone anabolism
eLife 12:e82142.
https://doi.org/10.7554/eLife.82142
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