This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 22/2/430    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pavel, E. Articles by Kirschner, L. S. Search for Related Content PubMed PubMed Citation Articles by Pavel, E. Articles by Kirschner, L. S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Medline Plus Health Information Bone Cancer

Mutation of Prkar1a Causes Osteoblast Neoplasia Driven by Dysregulation of Protein Kinase A

Department of Molecular Virology, Immunology, and Molecular Genetics (E.P., K.N., W.H.T., L.S.K.) and Division of Endocrinology (L.S.K.), Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Lawrence S. Kirschner, 420 West 12th Avenue, TMRF 546, Columbus, Ohio 43210. E-mail: Lawrence.Kirschner{at}osumc.edu.

Carney complex (CNC) is an autosomal dominant neoplasia syndrome caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A (PKA). This genetic defect induces skin pigmentation, endocrine tumors, myxomas, and schwannomas. Some patients with the complex also develop myxoid bone tumors termed osteochondromyxomas. To study the link between the PRKAR1A mutations and tumor formation, we generated a mouse model of this condition. Prkar1a^+/– mice develop bone tumors with high frequency, although these lesions have not yet been characterized, either from human patients or from mice. Bone tumors from Prkar1a^+/– mice were heterogeneous, including elements of myxomatous, cartilaginous, and bony differentiation that effaced the normal bone architecture. Immunohistochemical analysis identified an osteoblastic origin for the abnormal cells associated with islands of bone. To better understand these cells at the biochemical level, we isolated primary cultures of tumoral bone and compared them with cultures of bone from wild-type animals. The tumor cells exhibited the expected decrease in Prkar1a protein and exhibited increased PKA activity. At the phenotypic level, we observed that tumor cells behaved as incompletely differentiated osteoblasts and were able to form tumors in immunocompromised mice. Examination of gene expression revealed down-regulation of markers of bone differentiation and increased expression of locally acting growth factors, including members of the Wnt signaling pathway. Tumor cells exhibited enhanced growth in response to PKA-stimulating agents, suggesting that tumorigenesis in osteoblast precursor cells is driven by effects directly mediated by the dysregulation of PKA.