期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 21, 期 4, 页码 596-604出版社
WILEY
DOI: 10.1359/JBMR.051216
关键词
Fra1; AP-1; bone matrix; thrombospondin; osteoblast
资金
- NIAMS NIH HHS [AR45418, AR8562] Funding Source: Medline
Fra1 transgenic (Tg) mice develop osteosclerosis and exhibit altered expression of bone matrix proteins. We found that expression of Thbs1 and Tltbs2 was reduced in Fra1 Tg osteoblasts. Fra1 Tg and non-osteosclerotic Thbs1(-/-)Thbs2(-/-) mice share an edge-to-edge bite. Therefore, reduced expression of thrombospondins may contribute to craniofacial dysmorphism independently of osteosclerosis. Introduction: Tg mice overexpressing Fra1., a component of the transcription factor activator protein-1 (AP-1), show progressive osteosclerosis caused by cell autonomous abnormalities in osteoblasts. The expression of several bone matrix proteins, including matrix gla protein, is dysregulated in Fra1 To osteoblasts. Materials and Methods: In osteoblastogenic cultures, altered bone matrix production by Fra1 overexpression was monitored using Alizarin red staining, quantitative RT-PCR, and Western blotting. Responsiveness to ovariectomy was examined by bone histomorphometry. Craniofacial parameters were measured on radiographs and using CT. Results: Thrombospondin-1 (Thbs1) and thrombospondin-2 (Thbs2) were reduced in Fra1 Tg osteoblasts differentiated in vitro and in bones from Fra1 Tg mice. Despite alterations in bone matrix proteins, ovariectomy induces high turnover bone loss in Fra1 Tg mice as in wildtype mice. Fra1 Tg mice, as well as Thbs1(-/-) Thbs2(-/-) mice, which do not show osteosclerosis, exhibit an edge-to-edge bite phenotype associated with craniofacial dysmorphism. Conclusions: These data suggest that reduced expression of thrombospondins in Fra1. Tg mice underlies craniofacial dysmorphism, independent of osteosclerosis.
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