OR31-2 Abnormal cAMP-Dependent Protein Kinase Activity Leads to Bone Tumors in Adult Mice but This Depends on the PKA Subunit Expressions

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR31-Novel Signaling Mechanisms and Bone Cell Biology
Basic
Monday, June 23, 2014: 11:30 AM-1:00 PM
Presentation Start Time: 11:45 AM
W475 (McCormick Place West Building)

Outstanding Abstract Award
Sisi Liu1, Saloustros Emmanouil1, Edward Mertz2, Paraskevi Salpea1, Jenna Shapiro1, Sergey Leikin2 and Constantine A Stratakis, MD3
1Section on Endocrinology and Genetics, NICHD, NIH, Bethesda, MD, 2Section on Physical Biochemistry, NICHD, NIH, Bethesda, MD, 3National Institutes of Health (NIH), Bethesda, MD
PRKAR1A, the gene for type-I regulatory subunit of protein kinase A (PKA) is mutated in Carney complex, a disease associated with bone tumors. A mouse model of Prkar1a haploinsufficiency (Prkar1a+/-) developed bone lesions due to bone stromal cell (BSC) expansion; when haploinsufficiency of Prkaca, the gene coding for PKA type I catalytic subunit was introduced onto the Prkar1a+/- background to generate Prkar1a+/-Prkaca+/- mice, more vertebral lesions were found, along with increased PKA-II to PKA-I ratio. We now report two mouse models heterozygous for PKA regulatory subunits 2a or 2b in the Prkar1a+/- background. They developed similar lesions with later time of onset and lower aggressiveness. In double heterozygous vertebrae, Raman microscopy revealed better bone organization and mineralization levels, indicating a partial rescue of lesion phenotype; calcein staining indicated higher new bone formation rates. Immunohistochemistry showed higher expression of osteogenic markers (runx2, osteocalcin, osterix and Dmp1) in double heterozygous lesions; FACS supported such findings. Inverted osteons, which is an abnormal pattern of new bone formation without an existing bone surface, were found in these mice; this can be responsible for new bone formation inside lesion area. Higher percentages of Type I collagen homotrimers were also found (8%-25% compared with 0%-6% in wide type). PKA activity and PKA subunits expressions were analyzed. Decreased PKA-II to PKA-I ratios were found in Prkar1a+/-Prkar2a+/- (PKA-II: PKA-I =1.62) and Prkar1a+/-Prkar2b+/- (PKA-II: PKA-I = 1.32) bones compared with Prkar1a+/- ones (PKA-II: PKA-I = 1.82).We have also found increased Cβ subunit expression transcriptionally (3.6 and 2.3 folds respectively) and translationally (2.5 and 3.7 folds respectively) in double heterozygous lesions. In conclusion, decreased PKA-II to PKA-I ratios and increased Cβ subunit expression may contribute to higher osteogenic activity, resulting in better bone organization, mineralization and new bone formation in adult mice.

Nothing to Disclose: SL, SE, EM, PS, JS, SL, CAS

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