{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:10:09Z","timestamp":1789848609699,"version":"4.0.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2003,8,1]],"date-time":"2003-08-01T00:00:00Z","timestamp":1059696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>An activation mutation in the FGFR3 gene causes ACH. The effects of the FGFR3 mutants on apoptosis were analyzed in a chondrogenic cell line. ACH chondrocytes exhibited marked apoptotic with downregulation of PTHrP expression. Rescue of these cells by PTHrP replacement implies a potential therapy for this disorder.<\/jats:p>\n               <jats:p>Introduction: Achondroplasia (ACH), the most common form of short-limb dwarfism, and its related disorders are caused by constitutively activated point-mutated FGFR3. Recent studies have provided a large body of evidence on chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes.<\/jats:p>\n               <jats:p>Methods: The mutant FGFR3 genes causing ACH and thanatophoric dysplasia (TD), which is a more severe neonatal lethal form, were introduced into a chondrogenic cell line, ATDC5. Analysis of apoptosis was estimated by TUNEL assay, DNA laddering, and fluorescent measurement of mitochondrial membrane potential. Expression levels of parathyroid hormone-related peptide (PTHrP) and apoptosis-related genes were analyzed by Northern blot or immunoblot.<\/jats:p>\n               <jats:p>Results: The introduction of these mutated FGFR3s into ATDC5 cells downregulated PTHrP expression and induced apoptosis with reduction of Bcl-2 expression. Importantly, replacement of PTHrP prevented the apoptotic changes and reduction of Bcl-2 expression in ATDC5 cells expressing the ACH mutant. In parallel with the severity of disease and the activity of FGFR3, ATDC5 cells expressing TD-mutant FGFR3 showed less expression of PTHrP and Bcl-2 and induced more remarkable apoptotic changes compared with ACH-mutant expressing cells. Furthermore, overexpression of Bcl-2 inhibited apoptotic changes, suggesting that the mutant FGFR3 caused apoptosis, at least in part, through reduction of Bcl-2 expression, which seems to be downstream of PTHrP.<\/jats:p>\n               <jats:p>Conclusions: Our data suggest that excessive activation of signaling cascades mediated by the FGFR3 mutants inhibits the expression of PTHrP and Bcl-2, resulting in apoptosis of chondrocytes, possibly leading to short-limb dwarfism. Rescue of these cells by PTHrP replacement implies a potential therapy for this disorder.<\/jats:p>","DOI":"10.1359\/jbmr.2003.18.8.1395","type":"journal-article","created":{"date-parts":[[2006,4,27]],"date-time":"2006-04-27T05:55:56Z","timestamp":1146117356000},"page":"1395-1403","source":"Crossref","is-referenced-by-count":24,"title":["PTHrP Rescues ATDC5 Cells From Apoptosis Induced by FGF Receptor 3 Mutation"],"prefix":"10.1093","volume":"18","author":[{"given":"Yoshitaka","family":"Yamanaka","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, Okayama, 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