{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:42:50Z","timestamp":1768520570617,"version":"3.49.0"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T00:00:00Z","timestamp":1646438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israeli Science Foundation","award":["382\/13"],"award-info":[{"award-number":["382\/13"]}]},{"name":"NIH\/NIDCR","award":["DE019902"],"award-info":[{"award-number":["DE019902"]}]},{"name":"NIH\/NIDCR","award":["DE019902-04S1"],"award-info":[{"award-number":["DE019902-04S1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1\u03b1+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis.<\/jats:p>","DOI":"10.3390\/cells11050897","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:35:50Z","timestamp":1646598950000},"page":"897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling"],"prefix":"10.3390","volume":"11","author":[{"given":"Doron","family":"Cohn-Schwartz","sequence":"first","affiliation":[{"name":"Department of Internal Medicine B, Division of Internal Medicine, Rambam Healthcare Campus, Haifa 3109601, Israel"},{"name":"Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeshai","family":"Schary","sequence":"additional","affiliation":[{"name":"Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eran","family":"Yalon","sequence":"additional","affiliation":[{"name":"Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoe","family":"Krut","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Da","sequence":"additional","affiliation":[{"name":"Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4854-9698","authenticated-orcid":false,"given":"Edward M.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"The Center for Musculoskeletal Research, Department of Orthopaedics, School of Medicine & Dentistry, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Gazit","sequence":"additional","affiliation":[{"name":"Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gadi","family":"Pelled","sequence":"additional","affiliation":[{"name":"Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9176-0889","authenticated-orcid":false,"given":"Zulma","family":"Gazit","sequence":"additional","affiliation":[{"name":"Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e162775","DOI":"10.1001\/jamasurg.2016.2775","article-title":"Epidemiology of Fracture Nonunion in 18 Human 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