Reduced expression of thrombospondins and craniofacial dysmorphism in mice overexpressing Fra1

Toru Nishiwaki, Toru Yamaguchi, Chen Zhao, Hitoshi Amano, Kurt D. Hankenson, Paul Bornstein, Yoshiaki Toyama, Koichi Matsuo

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Fra1 transgenic (Tg) mice develop osteosclerosis and exhibit altered expression of bone matrix proteins. We found that expression of Thbs1 and Thbs2 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 Tg 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.

Original languageEnglish
Pages (from-to)596-604
Number of pages9
JournalJournal of Bone and Mineral Research
Issue number4
Publication statusPublished - 2006 Apr


  • AP-1
  • Bone matrix
  • Fra1
  • Osteoblast
  • Thrombospondin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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