C-MYB PROTOONCOGENE IS EXPRESSED BY QUIESCENT SCLERODERMA FIBROBLASTSAND, UNLIKE B-MYB GENE, DOES NOT CORRELATE WITH PROLIFERATION

Systemic sclerosis (scleroderma) is characterized by excessive deposit ion of extracellular matrix constituents. Although it has been propose d that tissue fibrosis is due to increased fibroblast synthesis of var ious collagen polypeptides, there is some experimental evidence that p atients with systemic sclerosis have a defect in the control of fibrob last growth. The myb family of genes includes, among others, the c-myb proto-oncogene and the structurally related gene, B-myb, which are bo th implicated in the regulation of differentiation and/or proliferatio n of hematopoietic and nonhematopoietic cells. To elucidate the molecu lar basis responsible for scleroderma fibroblast proliferation, we the refore elected to investigate the expression of c-myb and B-myb genes in scleroderma and control cells. Using the reverse transcriptase poly merase chain reaction technique, we detected c-myb transcripts in scle roderma skin fibroblasts rendered quiescent by serum deprivation. Unde r the same experimental conditions, c-myb message was not found in nor mal skin fibroblasts, but, after serum stimulation, c-myb RNA was clea rly evident from 3 to 72 h in both normal and pathologic cells, Treatm ent of these cells with c-myb antisense oligonucleotides caused downre gulation of c-myb expression, and the inhibition of scleroderma fibrob last proliferation was 42%, whereas in normal fibroblasts the inhibiti on was weaker (22%), In contrast to c-myb, in normal and scleroderma f ibroblasts the level of expression of B-myb correlated with cell proli feration assessed by cell count, and densitometric analysis showed tha t B-myb message was 1.5-5 times higher in most of pathologic cells stu died, The antisense B-myb oligonucleotides had a weaker antiproliferat ive effect compared with antisense c-myb, inhibiting scleroderma and n ormal fibroblasts by 23% and 13%, respectively. These data suggest tha t the B-myb and c-myb genes may play a role in scleroderma fibroblast proliferation and function.