The expression of the c-fos proto-oncogene during normal and pathological bone development was studied. The regulation of c-fos expression in bone cells by calcitriol and its contribution to the etiology of fibrous dysplasia was addressed. We have shown that treatment of osteoblasts with calcitriol, the active form of vitamin D, transiently stimulated the expression of c-fos, fos-B, c-jun and jun-B in a specific and dose-dependent manner. The expression of the Fos protein correlated with the expression of the c-fos gene. Finally, calcitriol appeared to modulate c-fos transcription in osteoblasts, whereas it stimulated c-jun and jun-B expression by a post-transcriptional mechanism distinct from mRNA stabilization. The transcriptional stimulation of c-fos was explored further and we identified a novel vitamin D response element (VDRE) in the c-fos promoter. We report that a 36 bp sequence centered around position-161 upstream of the c-fos transcription start site is responsive to 1,25-(OH)$ rm sb2D sb3$ in osteoblastic cells. This sequence binds the VDR, and mutations that abrogate binding to this element also abolish transcriptional activation by 1,25-(OH)$ sb2D sb3,$ demonstrating that we have identified a functional VDRE. Structure-function analysis revealed that the c-fos VDRE has an unusual structure that does not correspond to the classical direct repeat (DR)-type elements. Supporting this observation, our results show that the VDR requires a novel dimerizing partner to bind the c-fos VDRE. Finally, we report increased expression of c-fos in bone lesions from patients with fibrous dysplasia. The elevated c-fos mRNA levels were detected only in fibrous dysplasia lesions and not in samples from patients with other bone diseases where high bone turnover and fibrous marrow tissue are present. Our results support the implication of c-fos in the etiology of fibrous dysplasia.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.28429 |
| Date | January 1994 |
| Creators | Candelière, G. Antonio (Giuseppe Antonio) |
| Contributors | Arnaud, Rene St (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Surgical Research.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001413358, proquestno: NN00082, Theses scanned by UMI/ProQuest. |
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