title: Haploinsufficiency for either one of the type-II regulatory subunits of protein kinase A improves the bone phenotype of Prkar1a+/- mice.
abstract: Carney Complex (CNC), a human genetic syndrome predisposing to multiple neoplasias, is associated with bone lesions such as osteochondromyxomas (OMX). The most frequent cause for CNC is PRKAR1A deficiency; PRKAR1A codes for type-I regulatory subunit of protein kinase A (PKA). Prkar1a(+/-) mice developed OMX, fibrous dysplasia-like lesions (FDL) and other tumors. Tumor tissues in these animals had increased PKA activity due to an unregulated PKA catalytic subunit and increased PKA type II (PKA-II) activity mediated by the PRKAR2A and PRKAR2B subunits. To better understand the effect of altered PKA activity on bone, we studied Prkar2a and Prkar2b knock out (KO) and heterozygous mice; none of these mice developed bone lesions. When Prkar2a(+/-) and Prkar2b(+/-) mice were used to generate Prkar1a(+/-)Prkar2a(+/-) and Prkar1a(+/-)Prkar2b(+/-) animals, bone lesions formed that looked like those of the Prkar1a(+/-) mice. However, better overall bone organization and mineralization and fewer FDL lesions were found in both double heterozygote groups, indicating a partial restoration of the immature bone structure observed in Prkar1a(+/-) mice. Further investigation indicated increased osteogenesis and higher new bone formation rates in both Prkar1a(+/-)Prkar2a(+/-) and Prkar1a(+/-)Prkar2b(+/-) mice with some minor differences between them. The observations were confirmed with a variety of markers and studies. PKA activity measurements showed the expected PKA-II decrease in both double heterozygote groups. Thus, haploinsufficiency for either of PKA-II regulatory subunits improved bone phenotype of mice haploinsufficient for Prkar1a, in support of the hypothesis that the PRKAR2A and PRKAR2B regulatory subunits were in part responsible for the bone phenotype of Prkar1a(+/-) mice.
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Sisi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.affiliation: Section on Physical Biochemistry, Office of the Scientific Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Mertz
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Kitman
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Office of Research Services (ORS), Division of Veterinary Resources (DVR), Office of the Director (OD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Salpea
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.affiliation: Section on Physical Biochemistry, Office of the Scientific Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and.
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.affiliation: Section on Endocrinology and Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), stratakc@mail.nih.gov.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002113:Calcification, Physiologic; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000235:genetics*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism; D057895:Haploinsufficiency; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000943:Antigens, Differentiation; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517819:PRKAR2A protein, human; C517835:Prkar1a protein, mouse; D020033:Protein Isoforms