Activation of Protein Kinase A in Mature Osteoblasts Promotes a Major Bone Anabolic Response.
Protein kinase A (PKA) regulates osteoblast cell function in vitro and is activated by important bone mass modulating agents. We determined whether PKA activation in osteoblasts is sufficient to mediate a bone anabolic response. Thus, a mouse model conditionally expressing a constitutively active PKA (CA-PKA) in osteoblasts (CA-PKA-OB mouse) was developed by crossing a 2.3-kb α1 (I)-collagen promoter-Cre mouse with a floxed-CA-PKA mouse. Primary osteoblasts from the CA-PKA-OB mice exhibited higher basal PKA activity than those from control mice. Microcomputed tomographic analysis revealed that CA-PKA-OB female mice had an 8.6-fold increase in femoral but only 1.16-fold increase in lumbar 5 vertebral bone volume/total volume. Femur cortical thickness and volume were also higher in the CA-PKA-OB mice. In contrast, alterations in many femoral microcomputed tomographic parameters in male CA-PKA-OB mice were modest. Interestingly, the 3-dimensional structure model index was substantially lower both in femur and lumbar 5 of male and female CA-PKA-OB mice, reflecting an increase in the plate to rod-like structure ratio. In agreement, femurs from female CA-PKA-OB mice had greater load to failure and were stiffer compared with those of control mice. Furthermore, the CA-PKA-OB mice had higher levels of serum bone turnover markers and increased osteoblast and osteoclast numbers per total tissue area compared with control animals. In summary, constitutive activation of PKA in osteoblasts is sufficient to increase bone mass and favorably modify bone architecture and improve mechanical properties. PKA activation in mature osteoblasts is, therefore, an important target for designing anabolic drugs for treating diseases with bone loss.
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Liana
L
Tascau
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Thomas
T
Gardner
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Hussein
H
Anan
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Charlie
C
Yongpravat
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Christopher P
CP
Cardozo
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
William A
WA
Bauman
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Francis Y
FY
Lee
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Daniel S
DS
Oh
National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102.
Hesham A
HA
Tawfeek
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015519:Bone Density; D002478:Cells, Cultured; D004734:Energy Metabolism; D004789:Enzyme Activation; D005260:Female; D005269:Femur / Q000166:cytology* / Q000000981:diagnostic imaging / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000166:cytology* / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010012:Osteogenesis; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012727:Sex Characteristics; D015854:Up-Regulation; D055114:X-Ray Microtomography
C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases