A regulatory role of fibroblast growth factor in the expression of decorin, biglycan, betaglycan and syndecan in osteoblasts from patients with Crouzon's syndrome

Bone development is controlled by the autocrine and/or paracrine effects of regulatory molecules. We previously showed that the phenotype of fibroblas ts obtained from patients affected by Crouzon's syndrome, an autosomal domi nant disease characterized by pathological skull bone development, differed from that of normal cells and was regulated by interleukin treatments. The changes in the relative concentrations of extracellular macromolecules (gl ycosaminoglycans-GAG, collagen and fibronectin) were associated with abnorm al interleukin secretion that affected the microenvironment where the osteo genic processes take place. Mutations in human fibroblast growth factor rec eptors are now thought to be involved in Crouzon's syndrome. Since coactiva tion of interleukins and basic fibroblast growth factor (bFGF) is probably implicated in morphogenetic and osteogenic processes and heparan sulphate p roteoglycans have a critical role in regulating bFGF activity, the phenotyp es of normal and Crouzon osteoblasts were studied and the effects of bFGF o n the expression of bFGF, procollagen alpha(1) (I), and proteoglycan (PG) g enes for biglycan, decorin, betaglycan and syndecan analyzed. Specific huma n cDNA probes were used to screen the relative levels of mRNA by Northern a nalysis. Spontaneous or bFGF-modulated release of interleukins was also ass ayed. The bFGF gene transcript was detected only in Crouzon osteoblasts. We showed for the first time that Crouzon osteoblasts, despite a mutation in the FGF receptor, still responded to exogenous bFGF. In fact, the growth fa ctor induced changes in the GAG profile and in the levels of mRNA coding fo r PG and procollagen alpha(1) (I) and down-regulated heparan sulfate GAG ch ains. ELISA showed that bFGF-induced interleukin secretion differed in norm al and Crouzon osteoblasts. The observed differences in PG core protein, pr ocollagen alpha 1 (I) and bFGF could be associated with the Crouzon bone ph enotype and also should provide further understanding on the molecular basi s of the diseased state of bone.