Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

Kit Man Tsang, Matthew F. Starost, Maria Nesterova, Sosipatros A. Boikos, Tonya Watkins, Madson Q. Almeida, Michelle Harran, Andrew Li, Michael T. Collins, Christopher Cheadle, Edward L. Mertz, Sergey Leikin, Lawrence S. Kirschner, Pamela Robey, Constantine A. Stratakis

Research output: Contribution to journalArticle

Abstract

Apopulation of stromal cells that retains osteogenic capacity in adult bone (adult bone stromal cells or aBSCs) exists and is under intense investigation. Mice heterozygous for a null allele of prkar1a (Prkar1a+/-), the primary receptor for cyclic adenosine monophosphate (cAMP) and regulator of protein kinase A (PKA) activity, developed bone lesions that were derived from cAMP-responsive osteogenic cells and resembled fibrous dysplasia (FD). Prkar1a+/- mice were crossed with mice that were heterozygous for catalytic subunit Cα (Prkaca+/-), the main PKA activity-mediating molecule, to generate amousemodel withdouble heterozygosity for prkar1a and prkaca (Prkar1a+/-Prkaca+/-). Unexpectedly, Prkar1a+/-Prkaca+/- mice developed a greater number of osseous lesions starting at 3 months of age that varied from the rare chondromas in the long bones and the ubiquitous osteochondrodysplasia of vertebral bodies to the occasional sarcoma in older animals. Cells from these lesions originated from an area proximal to the growth plate, expressed osteogenic cell markers, and showed higher PKA activity that was mostly type II (PKA-II) mediated by an alternate pattern of catalytic subunit expression. Gene expression profiling confirmed a preosteoblastic nature for these cells but also showed a signature that was indicative of mesenchymal-to-epithelial transition and increased Wnt signaling. These studies show that a specific subpopulation of aBSCs can be stimulated in adult bone by alternate PKA and catalytic sub-unit activity; abnormal proliferation of these cells leads to skeletal lesions that have similarities to human FD and bone tumors.

Original languageEnglish (US)
Pages (from-to)8683-8688
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number19
DOIs
StatePublished - May 11 2010

Keywords

  • Catalytic subunit
  • Mesenchymal cells
  • Regulatory subunit
  • Sarcoma
  • Tumor

ASJC Scopus subject areas

  • General

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  • Cite this

    Tsang, K. M., Starost, M. F., Nesterova, M., Boikos, S. A., Watkins, T., Almeida, M. Q., Harran, M., Li, A., Collins, M. T., Cheadle, C., Mertz, E. L., Leikin, S., Kirschner, L. S., Robey, P., & Stratakis, C. A. (2010). Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone. Proceedings of the National Academy of Sciences of the United States of America, 107(19), 8683-8688. https://doi.org/10.1073/pnas.1003680107