Apert's syndrome: differential in vitro production of matrix macromolecules and its regulation by interleukins.

Abstract

During embryonic development, variations in the composition of the extracellular matrix (ECM) macromolecules influence bone tissue differentiation. We present novel findings on the in vitro phenotypic expression of periosteal fibroblasts obtained from patients affected by Apert's syndrome, a rare craniofacial malformation, and the effects that interleukins (ILs) induce on the phenotype. Apert fibroblasts synthesized greater quantities of glycosaminoglycans (GAGs) and intracellular type I collagen, and also produced more type III collagen and fibronectin. The amount of hyaluronic acid (HA) secreted by Apert fibroblasts was much higher than that secreted by normal fibroblasts, but, as the absolute values of heparan sulphate (HS), chondroitin sulphate (CS) and dermatan sulphate (DS) also rose in Apert media, the HA-sulphated GAG ratio was similar in the media obtained from both populations. Both ILs triggered elevations of HA in normal cells, although relative percentage secretion remained unaltered, but significantly reduced HA secretion by Apert cells. IL-1 significantly increased CS in normal and Apert media, whereas IL-6 enhanced HS and DS in media of both populations. HA-sulphated GAG ratio decreased in Apert media after IL treatment. Both ILs boosted fibronectin production by Apert fibroblasts, whereas IL-1 increased type III but not type I collagen. Taken together, these data demonstrate that the synthesis and secretion of ECM macromolecules are markedly altered in Apert fibroblasts. The fact that treatment with ILs further modifies the Apert phenotype suggests that ILs may be implicated in the pathophysiology of the malformations during skull morphogenesis.