MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/82142 |
| _version_ | 1797861360357343232 |
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| author | Tsz Long Chu Peikai Chen Anna Xiaodan Yu Mingpeng Kong Zhijia Tan Kwok Yeung Tsang Zhongjun Zhou Kathryn Song Eng Cheah |
| author_facet | Tsz Long Chu Peikai Chen Anna Xiaodan Yu Mingpeng Kong Zhijia Tan Kwok Yeung Tsang Zhongjun Zhou Kathryn Song Eng Cheah |
| author_sort | Tsz Long Chu |
| collection | DOAJ |
| description | 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, that 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 that 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. |
| first_indexed | 2024-04-09T22:02:18Z |
| format | Article |
| id | doaj.art-8263d27eb26f4eaca011192e0d5436a5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T22:02:18Z |
| publishDate | 2023-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8263d27eb26f4eaca011192e0d5436a52023-03-23T17:37:38ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.82142MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolismTsz Long Chu0https://orcid.org/0000-0001-8553-6880Peikai Chen1https://orcid.org/0000-0003-1880-0893Anna Xiaodan Yu2Mingpeng Kong3Zhijia Tan4https://orcid.org/0000-0003-2295-5169Kwok Yeung Tsang5Zhongjun Zhou6https://orcid.org/0000-0001-7092-8128Kathryn Song Eng Cheah7https://orcid.org/0000-0003-0802-8799School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong Kong; Department of Physiology and Pharmacology, Karolinska Institutet, Solna, SwedenSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong Kong; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong KongSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong KongSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong Kong; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong KongSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong KongSchool of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong SAR, Hong KongBone 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, that 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 that 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.https://elifesciences.org/articles/82142osteogenesisbone masschondrocyte-osteoblast lineageparathyroid hormone signalingmetalloproteinases |
| spellingShingle | Tsz Long Chu Peikai Chen Anna Xiaodan Yu Mingpeng Kong Zhijia Tan Kwok Yeung Tsang Zhongjun Zhou Kathryn Song Eng Cheah MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism eLife osteogenesis bone mass chondrocyte-osteoblast lineage parathyroid hormone signaling metalloproteinases |
| title | MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism |
| title_full | MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism |
| title_fullStr | MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism |
| title_full_unstemmed | MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism |
| title_short | MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism |
| title_sort | mmp14 cleaves pth1r in the chondrocyte derived osteoblast lineage curbing signaling intensity for proper bone anabolism |
| topic | osteogenesis bone mass chondrocyte-osteoblast lineage parathyroid hormone signaling metalloproteinases |
| url | https://elifesciences.org/articles/82142 |
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