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

  1. Tsz Long Chu
  2. Peikai Chen
  3. Anna Xiaodan Yu
  4. Mingpeng Kong
  5. Zhijia Tan
  6. Kwok Yeung Tsang
  7. Zhongjun Zhou
  8. Kathryn Song Eng Cheah  Is a corresponding author
  1. University of Hong Kong, Hong Kong
  2. 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.

The following data sets were generated

Article and author information

Author details

  1. Tsz Long Chu

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  2. Peikai Chen

    Department of Orthopaedics and Traumatology, University of Hong Kong - Shenzhen Hospital, Shenzhen, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1880-0893
  3. Anna Xiaodan Yu

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  4. Mingpeng Kong

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  5. Zhijia Tan

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2295-5169
  6. Kwok Yeung Tsang

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  7. Zhongjun Zhou

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7092-8128
  8. Kathryn Song Eng Cheah

    School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong
    For correspondence
    kathycheah@hku.hk
    Competing interests
    Kathryn Song Eng Cheah, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0802-8799

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.

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.

Reviewing Editor

  1. Di Chen, Chinese Academy of Sciences, China

Version history

  1. Received: July 25, 2022
  2. Preprint posted: August 17, 2022 (view preprint)
  3. Accepted: March 8, 2023
  4. Accepted Manuscript published: March 9, 2023 (version 1)
  5. 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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  1. Tsz Long Chu
  2. Peikai Chen
  3. Anna Xiaodan Yu
  4. Mingpeng Kong
  5. Zhijia Tan
  6. Kwok Yeung Tsang
  7. Zhongjun Zhou
  8. Kathryn Song Eng Cheah
(2023)
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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