Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1

Abstract

Bone formation by osteoblasts is essential for skeletal growth and remodeling. Fra-1 is a c-Fos-related protein belonging to the AP-1 family of transcription factors. Here we show that transgenic mice overexpressing Fra-1 in various organs develop a progressive increase in bone mass leading to osteosclerosis of the entire skeleton, which is due to a cell-autonomous increase in the number of mature osteoblasts. Moreover, osteoblast differentiation, but not proliferation, was enhanced and osteoclastogenesis was also elevated in vitro. These data indicate that, unlike c-Fos, which causes osteosarcomas, Fra-1 specifically enhances bone formation, which may be exploited to stimulate bone formation in pathological conditions.

Estrogen-induced Expression of Fos-related Antigen 1 (FRA-1) Regulates Uterine Stromal Differentiation and Remodeling

“…This defect in differentiation is rescued by overexpression of FRA-1, suggesting overlapping functions of c-Fos and FRA-1 in osteoclast differentiation (25). Additionally, ectopic expression of FRA-1 accelerates differentiation of osteoprogenitors to mature osteoblasts (26). Consistent with these observations, development of a conditional knock-out model of Fra-1 confirmed its critical role in osteoblast differentiation (27).…”

Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements

“…Consistent with these observations, a high level of fra-1 expression is found in various tumors and tumorogenic cell lines (Matsui et al, 1990;Hu et al, 2001;Zajchowski et al, 2001;. Indeed, fra-1 transgenic mice develop lung tumors (Jochum et al, 2000). Several lines of recent evidence have also indicated a potential role for FRA-1 in abnormal differentiation and transformation of lung cells.…”

A mouse model of adult-onset anaemia due to erythropoietin deficiency

“…Osteoblast progenitors were prepared from neonatal (3 À 5 days old) mouse calvariae that were sequentially digested with 0.1% collagenase (Worthington Biochemical Corporation) in aminimum essential medium (Sigma). The cells expanded in aminimum essential medium containing 10% fetal bovine serum for 2 days were differentiated into osteoblasts by supplementation of b-glycerophosphate (10 mM), dexamethasone (0.1 mM) and ascorbate (50 mg ml -1 ) for a week 58 . Alkaline phosphatase staining (AP staining kit, Stemgent) confirmed that the purity of mature osteoblasts was 470%.…”