SELECTIVE EXPRESSION OF FOS-RELATED AND JUN-RELATED GENES DURING OSTEOBLAST PROLIFERATION AND DIFFERENTIATION

Developmental studies of oncogene expression and transgenic animal stu dies implicate c-fos and other fos and jun family members in the regul ation of bone tissue formation. Therefore, to initiate experimental ex amination of the hypothesis that expression of fos- and jun-related ge nes is functionally coupled to modulation of gene expression which sup ports bone development, we determined levels of expression of the prin ciple fos and jun family members during progressive differentiation of normal rat calvaria-derived osteoblasts within two contexts. First, c ellular mRNA levels were quantitated under conditions where expression of serum-induced early response genes had returned to basal levels. O ur findings demonstrate high levels of c-fos, c-jun, and jun B mRNA tr anscripts during the proliferative period of osteoblast development, w hile expression of fra-1 and fra-2 is enhanced during the differentiat ion period. jun D is constitutively expressed during the time course e xhibiting only a 30% decline in levels postproliferatively, and fos B mRNA is undetectable by Northern blot analyses. Late in the developmen tal sequence, apoptosis is evident. At this time, fra-1 expression is completely downregulated, while c-fos, fra-2, c-jun, jun B, and jun D show a dramatic enhancement in expression. Second, we addressed differ ential expression of fos and jun family members in relation to serum r esponsiveness as a function of stages of phenotypic development. Proli ferating cells exhibit a prolonged induction of fos and jun family mem bers in response to serum. While in differentiated cells, which are re fractory to growth stimulus even when exposed to fresh serum every 2 d ays, a spike in fos and jun expression is observed. Thus, our data dem onstrate significant differences in basal and serum responsiveness of fos and jun family members over the course of osteoblast differentiati on. These findings are consistent with multiple lines of evidence link ing activity of these early response genes to regulation of cell growt h and development of the bone tissue phenotype. (C) 1995 Acndemic Pres s, Inc.