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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\n                    <jats:italic>Mmp14<\/jats:italic>\n                    global knockouts, postnatal day 10 (p10) HC lineage-specific\n                    <jats:italic>Mmp14<\/jats:italic>\n                    null mutants (Mmp14\u0394HC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling, and consistent with the implied regulatory role, in Mmp14\u0394HC mutants, PTH signaling is enhanced. We found that HC-derived osteoblasts contribute ~50% of osteogenesis promoted by treatment with PTH 1\u201334, and this response was amplified in Mmp14\u0394HC. 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.82142","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T08:00:53Z","timestamp":1678348853000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82142","source":"Crossref","is-referenced-by-count":21,"title":["MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-6880","authenticated-orcid":true,"given":"Tsz Long","family":"Chu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, University of Hong Kong, Pokfulam","place":["Hong Kong SAR, Hong Kong"]},{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Pharmacology, Karolinska Institutet","place":["Solna, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1880-0893","authenticated-orcid":true,"given":"Peikai","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, University of Hong Kong, Pokfulam","place":["Hong Kong SAR, Hong Kong"]},{"id":[{"id":"https:\/\/ror.org\/047w7d678","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Xiaodan","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, University of Hong Kong, Pokfulam","place":["Hong Kong SAR, Hong Kong"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingpeng","family":"Kong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, University of Hong Kong, Pokfulam","place":["Hong Kong SAR, Hong Kong"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2295-5169","authenticated-orcid":true,"given":"Zhijia","family":"Tan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, University of Hong Kong, Pokfulam","place":["Hong Kong SAR, Hong 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