Activating mutations of the alpha chain of the heterotrimeric signal transducer Gs disrupt the inherent guanosine triphosphatase activity of the alpha chain, stimulate adenylyl cyclase, and can result in independent cell proliferation. Such mutations are identified in a number of endocrine disorders, including McCune-Albright syndrome, which is a triad of endocrinopathy, café au lait spots, and polyostotic fibrous dysplasia. The mutation in this syndrome is a missense point mutation in exon 8 that results in the substitution of either histidine or cysteine for arginine at position 201. Monostotic fibrous dysplasia is a nonhereditary isolated bone lesion. Other isolated bone lesions that share some cytologic and clinical similarities to fibrous dysplasia are osteofibrous dysplasia and aggressive fibromatosis involving bone. Four cases of monostotic fibrous dysplasia, four cases of aggressive fibromatosis involving bone, and one case of osteofibrous dysplasia were studied to determine if a mutation was present in exon 8 of the alpha chain of Gs. A missense mutation was present in all of the fibrous dysplasias. The other fibrous lesions and uninvolved tissue did not contain a mutation. Somatic activating mutations of Gs differentiate fibrous dysplasia from the other lesions and may be responsible for the loss of control of local proliferation and growth factor expression.
Palmar fibromatosis (Dupuytren contracture) causes fibrosis of specific palmar fascial bands. These bands are subjected to repetitive mechanical strain in situ. Primary cell cultures were derived from (a) palmar fibromatosis from eight patients, (b) uninvolved palmar fascia (Skoog's fibers) from four of these patients, and (c) normal palmar fascia from four additional patients. The cells were plated onto collagen-coated membranes either subjected to cyclic strain (25% maximal strain at 1 Hz) or without strain. Bromodeoxyuridine incorporation showed an increase in proliferation in all cultures subjected to strain. This increase was highest for palmar fibromatosis (10 to 40% nuclear incorporation, p = 0.02). Skoog's fibers and fascia from the normal individuals showed a trend (not significant) toward increase with strain (8 to 25%, p = 0.15 for Skoog's fibers, and 8 to 15%, p = 0.45 for normal fascia). Cyclic strain increased the expression of platelet-derived growth factor-A relative to glyceraldehyde-3-phosphate dehydrogenase in palmar fibromatosis (2.2 to 3.5, p = 0.05) and Skoog's fibers (0.8 to 2.0, p = 0.04). The expression of platelet-derived growth factor-B relative to glyceraldehyde-3-phosphate dehydrogenase was enhanced by cyclic strain only in the fibromatosis tissue (0.7 to 2.1, p = 0.04). The normal fascia did not express platelet-derived growth factor. Platelet-derived growth factor neutralizing antibody decreased bromodeoxyuridine incorporation in fibromatosis cultures subjected to cyclic strain to near levels for those grown in the absence of strain (38 to 16%, p = 0.05). Conditioned medium from fibromatosis cells grown under stain showed a trend toward increased proliferation in additional fibromatosis cultures compared with conditioned medium from fibromatosis cells grown without strain (9 to 15% nuclear incorporation, p = 0.20). The observed palmar fibromatosis contracture can be partially explained on the basis of the cell's response to cyclic strain, which may be mediated by platelet-derived growth factor.
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