Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone.
A population 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 Calpha (Prkaca(+/-)), the main PKA activity-mediating molecule, to generate a mouse model with double 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 subunit activity; abnormal proliferation of these cells leads to skeletal lesions that have similarities to human FD and bone tumors.
Tsang
Kit Man
KM
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Starost
Matthew F
MF
Nesterova
Maria
M
Boikos
Sosipatros A
SA
Watkins
Tonya
T
Almeida
Madson Q
MQ
Harran
Michelle
M
Li
Andrew
A
Collins
Michael T
MT
Cheadle
Christopher
C
Mertz
Edward L
EL
Leikin
Sergey
S
Kirschner
Lawrence S
LS
Robey
Pamela
P
Stratakis
Constantine A
CA
D000375:Aging / Q000473:pathology*; D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology*; D002113:Calcification, Physiologic; D020134:Catalytic Domain; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism*; D006579:Heterozygote; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013059:Spectrum Analysis, Raman; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D014057:Tomography, X-Ray Computed
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517758:Prkaca protein, mouse; D010727:Phosphoric Diester Hydrolases