This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riminucci, M. Articles by Gehron Robey, P. Search for Related Content PubMed PubMed Citation Articles by Riminucci, M. Articles by Gehron Robey, P.

American Journal of Pathology, Vol 151, 1587-1600, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation

M Riminucci, LW Fisher, A Shenker, AM Spiegel, P Bianco and P Gehron Robey
Craniofacial and Skeletal Diseases Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA.

In addition to cafe-au-lait pigmentation patterns and hyperendocrinopathies, fibrous dysplasia of bone is a major finding in the McCune-Albright syndrome. Activating missense mutations of the Gs alpha gene leading to overactivity of adenylyl cyclase have been identified in patients with McCune-Albright syndrome, but the mechanism leading to the specific development of fibrous dysplasia in bone has not been elucidated. By means of specific peptide antisera and reverse transcriptase polymerase chain reaction in situ hybridization, we show that expression of Gs alpha and its mRNA is critically up-regulated during maturation of precursor osteogenic cells to normal osteoblast cells and that this pattern of expression is retained in fibrous dysplasia. A functional characterization of fibrous dysplastic tissues revealed that the fibrotic areas consist, in fact, of an excess of cells with phenotypic features of pre-osteogenic cells, whereas the lesional bone formed de novo within fibrotic areas represents the biosynthetic output of mature but abnormal osteoblasts. These cells are noted for peculiar changes in cell shape and interaction with matrix, which were mimicked in vitro by the effects of excess exogenous cAMP on human osteogenic cells. Osteoblasts involved with the de novo deposition of lesional bone in fibrous dysplasia produce a bone matrix enriched in certain anti-adhesion molecules (versican and osteonectin), and poor in the pro-adhesive molecules osteopontin and bone sialoprotein, which is in contrast to the high levels of these two proteins found in normal de novo bone. Our data indicate the need to reinterpret fibrous dysplasia of bone as a disease of cells in the osteogenic lineage, related to the effects of excess cAMP on bone cell function. They further suggest that a critical, physiological, maturation-related regulation of Gs alpha levels makes cells in the osteogenic lineage a natural target for the effects of mutations in the Gs alpha gene and may provide a clue as to why bone itself is affected in this somatic, mutation-dependent disease.

This article has been cited by other articles:

				E. Pavel, K. Nadella, W. H. Towns II, and L. S. Kirschner Mutation of Prkar1a Causes Osteoblast Neoplasia Driven by Dysregulation of Protein Kinase A Mol. Endocrinol., February 1, 2008; 22(2): 430 - 440. [Abstract] [Full Text] [PDF]

				S. Michienzi, N. Cherman, K. Holmbeck, A. Funari, M. T. Collins, P. Bianco, P. G. Robey, and M. Riminucci GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs{alpha} Hum. Mol. Genet., August 15, 2007; 16(16): 1921 - 1930. [Abstract] [Full Text] [PDF]

				L. S. Kirschner, D. F. Kusewitt, L. Matyakhina, W. H. Towns II, J. A. Carney, H. Westphal, and C. A. Stratakis A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP-Responsive Tissues Cancer Res., June 1, 2005; 65(11): 4506 - 4514. [Abstract] [Full Text] [PDF]

				S. A. Kuznetsov, M. Riminucci, N. Ziran, T. W. Tsutsui, A. Corsi, L. Calvi, H. M. Kronenberg, E. Schipani, P. G. Robey, and P. Bianco The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow J. Cell Biol., December 20, 2004; 167(6): 1113 - 1122. [Abstract] [Full Text] [PDF]

				H. Plotkin, F. Rauch, L. Zeitlin, C. Munns, R. Travers, and F. H. Glorieux Effect of Pamidronate Treatment in Children with Polyostotic Fibrous Dysplasia of Bone J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4569 - 4575. [Abstract] [Full Text] [PDF]

				J. S. Lee, E. FitzGibbon, J. A. Butman, C. R. Dufresne, H. Kushner, S. Wientroub, P. G. Robey, and M. T. Collins Normal Vision despite Narrowing of the Optic Canal in Fibrous Dysplasia N. Engl. J. Med., November 21, 2002; 347(21): 1670 - 1676. [Abstract] [Full Text] [PDF]

				L. S. WEINSTEIN, M. CHEN, and J. LIU Gs{alpha} Mutations and Imprinting Defects in Human Disease Ann. N.Y. Acad. Sci., June 1, 2002; 968(1): 173 - 197. [Abstract] [Full Text] [PDF]

				L. S. Weinstein, S. Yu, D. R. Warner, and J. Liu Endocrine Manifestations of Stimulatory G Protein {alpha}-Subunit Mutations and the Role of Genomic Imprinting Endocr. Rev., October 1, 2001; 22(5): 675 - 705. [Abstract] [Full Text] [PDF]

				A. Sakamoto, Y. Oda, Y. Iwamoto, and M. Tsuneyoshi A Comparative Study of Fibrous Dysplasia and Osteofibrous Dysplasia with Regard to GS{alpha} Mutation at the Arg201 Codon: Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Analysis of Paraffin-Embedded Tissues J. Mol. Diagn., May 1, 2000; 2(2): 67 - 72. [Abstract] [Full Text]

				H. KITOH, Y. YAMADA, and H. NOGAMI Different genotype of periosteal and endosteal cells of a patient with polyostotic fibrous dysplasia J. Med. Genet., September 1, 1999; 36(9): 724 - 725. [Full Text]