{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:34:49Z","timestamp":1790681689789,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T00:00:00Z","timestamp":1555027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR068983"],"award-info":[{"award-number":["R01AR068983"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AR072836"],"award-info":[{"award-number":["R21AR072836"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AR073331"],"award-info":[{"award-number":["R21AR073331"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1DP5OD021351"],"award-info":[{"award-number":["1DP5OD021351"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Qatar National Research Foundation","award":["NPRP 7-1301-3-336"],"award-info":[{"award-number":["NPRP 7-1301-3-336"]}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2014R1A6A3A03055719"],"award-info":[{"award-number":["2014R1A6A3A03055719"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1OsxMek2\u2212\/\u2212), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1Osx-ERTMek2\u2212\/\u2212) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and \u03b2-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation.<\/jats:p>","DOI":"10.3390\/ijms20081803","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T12:55:04Z","timestamp":1555073704000},"page":"1803","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":127,"title":["The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis"],"prefix":"10.3390","volume":"20","author":[{"given":"Jung-Min","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon-Suk","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2110-0559","authenticated-orcid":false,"given":"Kwang Hwan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwanhee","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B.","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4947-3293","authenticated-orcid":false,"given":"Jae-Hyuck","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA"},{"name":"Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/nrm3254","article-title":"Building strong bones: Molecular regulation of the osteoblast lineage","volume":"13","author":"Long","year":"2011","journal-title":"Nat. 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