Figure 5.

Model illustrates a series of regulatory steps that may cause inception and promotion of formation and growth of exostosis. A: The cells of most patients with hereditary multiple exostoses bear a heterozygous loss-of-function mutation in EXT1 or EXT2 (depicted here at Ext^+/− cells in half white and half red). B: At one point prenatally or postnatally, some cells may undergo a second genetic change (depicted here as red cells along perichondrium and called mutant in the text), resulting in a more severe loss of overall EXT expression or function and leading to further reduction in local HS production and levels. C: This in turn may up-regulate Hep'ase expression, increase growth factor availability and cell proliferation, and induce ectopic chondrogenesis near/at perichondrium. D: The incipient exostosis cells may recruit surrounding heterozygous cells, induce them into neoplastic behavior, and promote their incorporation into the outgrowing exostosis. E: Cells within the outgrowing exostosis may assemble into a typical growth plate-like structure that protrudes away from the surface of the skeletal element (depicted here as a long bone) and cover distally by perichondrium. By inhibiting heparanase activity and possibly other processes, SST may inhibit chondrogenesis and in turn exostosis formation as indicated. Surfen (not indicated here) may elicit the opposite and stimulate chondrogenesis. Hep'ase, heparanase; HS, heparan sulfate; SST, SST0001; Surfen, bis-2-methyl-4-aminoquinolyl-6-carbamide.