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Apert syndrome caused by gain\u2010of\u2010function mutations of FGFR2 results in aberrant phenotypes of the skull, midface, and limbs. Although short limbs are representative features in patients with Apert syndrome, the causative mechanism for this limb defect has not been elucidated. Here\u00a0we quantitatively confirmed decreases in the bone length, bone mineral density, and bone thickness in the Apert syndrome model of gene knock\u2010in <jats:italic>Fgfr2<\/jats:italic><jats:sup><jats:italic>S252W\/+<\/jats:italic><\/jats:sup> (<jats:italic>EIIA\u2010Fgfr2<\/jats:italic><jats:sup><jats:italic>S252W\/+<\/jats:italic><\/jats:sup>) mice. Interestingly, despite these bone defects, histological analysis showed that the endochondral ossification process in the mutant mice was similar to that in wild\u2010type mice. Tartrate\u2010resistant acid phosphatase staining revealed that trabecular bone loss in mutant mice was associated with excessive osteoclast activity despite accelerated osteogenic differentiation. We investigated the osteoblast\u2013osteoclast interaction and found that the increase in osteoclast activity was due to an increase in the <jats:italic>Rankl<\/jats:italic> level of osteoblasts in mutant mice and not enhanced osteoclastogenesis driven by the activation of FGFR2 signaling in bone marrow\u2010derived macrophages. Consistently, <jats:italic>Col1a1\u2010Fgfr2<\/jats:italic><jats:sup><jats:italic>S252W\/+<\/jats:italic><\/jats:sup> mice, which had osteoblast\u2010specific expression of <jats:italic>Fgfr2<\/jats:italic> S252W, showed significant bone loss with a reduction of the bone length and excessive activity of osteoclasts was observed in the mutant mice. Taken together, the present study demonstrates that the imbalance in osteoblast and osteoclast coupling by abnormally increased Rankl expression in <jats:italic>Fgfr2<\/jats:italic><jats:sup><jats:italic>S252W\/+<\/jats:italic><\/jats:sup> mutant osteoblasts is a major causative mechanism for bone loss and short long bones in <jats:italic>Fgfr2<\/jats:italic><jats:sup><jats:italic>S252W\/+<\/jats:italic><\/jats:sup> mice.<\/jats:p>","DOI":"10.1002\/jcp.30682","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T08:06:39Z","timestamp":1642665999000},"page":"2155-2168","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Excessive osteoclast activation by osteoblast paracrine factor RANKL is a major cause of the abnormal long bone phenotype in Apert syndrome model mice"],"prefix":"10.1002","volume":"237","author":[{"given":"Hye\u2010Rim","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Dental Pharmacology,\u00a0School of Dentistry and Dental Research Institute Seoul National University  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bong\u2010Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Dental Pharmacology,\u00a0School of Dentistry and Dental Research Institute Seoul National University  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun\u2010Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Dental Pharmacology,\u00a0School of Dentistry and Dental Research Institute Seoul National University  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heein","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Dental Pharmacology,\u00a0School of Dentistry and Dental Research Institute Seoul National University  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo\u2010Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Dental Pharmacology,\u00a0School of Dentistry and Dental Research Institute Seoul National University  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5057-8842","authenticated-orcid":false,"given":"Je\u2010Yong","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Skeletal Disease Analysis Center, Korea Mouse Phenotyping Center (KMPC), School of Medicine Kyungpook National University  Daegu South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6769-8341","authenticated-orcid":false,"given":"Hyun\u2010Mo","family":"Ryoo","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Dental Pharmacology,\u00a0School of Dentistry and Dental Research Institute Seoul National University  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1096\/fba.2020-00058"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.9.1475"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.081248"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006534-200112000-00030"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2014.06.001"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087311"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2001.16.11.2074"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320470509"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-321539"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304698200"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320450322"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rdc.2011.07.004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302457200"},{"key":"e_1_2_8_15_1","volume-title":"Developmental biology.\u00a0Osteogenesis: The development of bones","author":"Gilbert S. 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