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

Fingerprint

Stromal Cells
Cyclic AMP-Dependent Protein Kinases
Bone and Bones
Cyclic AMP
Population
Cyclic AMP-Dependent Protein Kinase Type II
Catalytic Domain
Fibrous Dysplasia of Bone
Osteochondrodysplasias
Chondroma
Epithelial-Mesenchymal Transition
Growth Plate
Gene Expression Profiling
Sarcoma
Alleles
Cell Proliferation
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone. / Tsang, Kit Man; Starost, Matthew F.; Nesterova, Maria; Boikos, Sosipatros A.; Watkins, Tonya; Almeida, Madson Q.; Harran, Michelle; Li, Andrew; Collins, Michael T.; Cheadle, Christopher; Mertz, Edward L.; Leikin, Sergey; Kirschner, Lawrence S.; Robey, Pamela; Stratakis, Constantine A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 19, 11.05.2010, p. 8683-8688.

Research output: Contribution to journalArticle

Tsang, KM, Starost, MF, Nesterova, M, Boikos, SA, Watkins, T, Almeida, MQ, Harran, M, Li, A, Collins, MT, Cheadle, C, Mertz, EL, Leikin, S, Kirschner, LS, Robey, P & Stratakis, CA 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, vol. 107, no. 19, pp. 8683-8688. https://doi.org/10.1073/pnas.1003680107
Tsang, Kit Man ; Starost, Matthew F. ; Nesterova, Maria ; Boikos, Sosipatros A. ; Watkins, Tonya ; Almeida, Madson Q. ; Harran, Michelle ; Li, Andrew ; Collins, Michael T. ; Cheadle, Christopher ; Mertz, Edward L. ; Leikin, Sergey ; Kirschner, Lawrence S. ; Robey, Pamela ; Stratakis, Constantine A. / Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 19. pp. 8683-8688.
@article{820ca80275fc4b698bb3dbd959ea0d26,
title = "Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone",
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.",
keywords = "Catalytic subunit, Mesenchymal cells, Regulatory subunit, Sarcoma, Tumor",
author = "Tsang, {Kit Man} and Starost, {Matthew F.} and Maria Nesterova and Boikos, {Sosipatros A.} and Tonya Watkins and Almeida, {Madson Q.} and Michelle Harran and Andrew Li and Collins, {Michael T.} and Christopher Cheadle and Mertz, {Edward L.} and Sergey Leikin and Kirschner, {Lawrence S.} and Pamela Robey and Stratakis, {Constantine A.}",
year = "2010",
month = "5",
day = "11",
doi = "10.1073/pnas.1003680107",
language = "English (US)",
volume = "107",
pages = "8683--8688",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "19",

}

TY - JOUR

T1 - Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

AU - Tsang, Kit Man

AU - Starost, Matthew F.

AU - Nesterova, Maria

AU - Boikos, Sosipatros A.

AU - Watkins, Tonya

AU - Almeida, Madson Q.

AU - Harran, Michelle

AU - Li, Andrew

AU - Collins, Michael T.

AU - Cheadle, Christopher

AU - Mertz, Edward L.

AU - Leikin, Sergey

AU - Kirschner, Lawrence S.

AU - Robey, Pamela

AU - Stratakis, Constantine A.

PY - 2010/5/11

Y1 - 2010/5/11

N2 - 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.

AB - 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.

KW - Catalytic subunit

KW - Mesenchymal cells

KW - Regulatory subunit

KW - Sarcoma

KW - Tumor

UR - http://www.scopus.com/inward/record.url?scp=77952692816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952692816&partnerID=8YFLogxK

U2 - 10.1073/pnas.1003680107

DO - 10.1073/pnas.1003680107

M3 - Article

C2 - 20421483

AN - SCOPUS:77952692816

VL - 107

SP - 8683

EP - 8688

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 19

ER -