. Protein kinase Cα (PKCα) Regulates Bone Architecture and Osteoblast Activity*. Journal of Biological Chemistry, 289(37), 25509-25522

Background: Roles of the multifunctional kinase PKC (cid:2) in bone are unknown. Results: Female Prkca (cid:2) / (cid:2) mice form bone in their medullary cavities associated with higher osteoblastic differentiation. Bone and spleen changes in Prkca (cid:2) / (cid:2) mice resemble features of Gaucher disease. Conclusion: PKC (cid:2) regulates osteoblast differentiation and bone architecture. Significance: PKC (cid:2) -targeting therapies may benefit low bone mass conditions, including Gaucher disease and osteoporosis. Bones’ strength is achieved and maintained through adaptation to load bearing. The role of the protein kinase PKC (cid:2) in this processhasnotbeenpreviouslyreported.However,weobserved a phenotype in the long bones of Prkca (cid:3) / (cid:3) female but not male mice, in which bone tissue progressively invades the medullary cavity in the mid-diaphysis. This bone deposition progresses with age and is prevented by disuse but unaffected by ovariectomy. Castration of male Prkca (cid:3) / (cid:3) but not WT mice results in the formation of small amounts of intramedullary bone. Osteoblast differentiation

[1]  L. Lanyon,et al.  Age-Related Impairment of Bones' Adaptive Response to Loading in Mice Is Associated With Sex-Related Deficiencies in Osteoblasts but No Change in Osteocytes , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  Christopher M. Williams,et al.  PKCα negatively regulates in vitro proplatelet formation and in vivo platelet production in mice , 2014, Platelets.

[3]  L. Lanyon,et al.  Estrogen receptors' roles in the control of mechanically adaptive bone (re)modeling. , 2013, BoneKEy reports.

[4]  J. Swift,et al.  β-1 adrenergic agonist mitigates unloading-induced bone loss by maintaining formation. , 2013, Medicine and science in sports and exercise.

[5]  Claes Ohlsson,et al.  Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2 , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[6]  Lance E. Lanyon,et al.  Estrogen Receptor α Mediates Proliferation of Osteoblastic Cells Stimulated by Estrogen and Mechanical Strain, but Their Acute Down-regulation of the Wnt Antagonist Sost Is Mediated by Estrogen Receptor β* , 2013, The Journal of Biological Chemistry.

[7]  J. Sands,et al.  Role of protein kinase C-α in hypertonicity-stimulated urea permeability in mouse inner medullary collecting ducts. , 2013, American journal of physiology. Renal physiology.

[8]  Lance E. Lanyon,et al.  Lrp5 Is Not Required for the Proliferative Response of Osteoblasts to Strain but Regulates Proliferation and Apoptosis in a Cell Autonomous Manner , 2012, PloS one.

[9]  William J Browne,et al.  Bones' Adaptive Response to Mechanical Loading Is Essentially Linear Between the Low Strains Associated With Disuse and the High Strains Associated With the Lamellar/Woven Bone Transition , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  L. Lanyon,et al.  Estrogen Receptors (cid:1) and (cid:2) Have Different Gender-Dependent Effects on the Adaptive Responses to Load Bearing in Cancellous and Cortical Bone , 2012 .

[11]  B. Williams,et al.  Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. , 2011, Developmental biology.

[12]  L. Lanyon,et al.  Loading-related Regulation of Transcription Factor EGR2/Krox-20 in Bone Cells Is ERK1/2 Protein-mediated and Prostaglandin, Wnt Signaling Pathway-, and Insulin-like Growth Factor-I Axis-dependent* , 2011, The Journal of Biological Chemistry.

[13]  Lance E. Lanyon,et al.  Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4 , 2011, FEBS letters.

[14]  W. Tomczak,et al.  Gaucher disease diagnosed after bone marrow trephine biopsy - a report of two cases. , 2011, Folia histochemica et cytobiologica.

[15]  L. E. Lanyon,et al.  Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered , 2011, Osteoporosis International.

[16]  T. Rachner,et al.  Osteoporosis: now and the future , 2011, The Lancet.

[17]  P. Marie,et al.  Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions , 2011, Aging cell.

[18]  Hiroumi Yoshikawa,et al.  PKCα suppresses osteoblastic differentiation. , 2011, Bone.

[19]  E. Posvar,et al.  Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  Hongyu Zhao,et al.  Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage , 2010, Proceedings of the National Academy of Sciences.

[21]  Lance E. Lanyon,et al.  Mechanical Loading-Related Bone Gain Is Enhanced by Tamoxifen but Unaffected by Fulvestrant in Female Mice , 2010, Endocrinology.

[22]  Y. Inoue,et al.  Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts , 2010, PloS one.

[23]  Ralph Müller,et al.  Guidelines for assessment of bone microstructure in rodents using micro–computed tomography , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[24]  Ego Seeman,et al.  Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study , 2010, The Lancet.

[25]  A. Poole,et al.  Protein kinase Cα: disease regulator and therapeutic target , 2010, Trends in pharmacological sciences.

[26]  S. Boonen,et al.  Androgen receptor disruption increases the osteogenic response to mechanical loading in male mice , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  Yoshiaki Kawano,et al.  Mechano-transduction in Osteoblastic Cells Involves Strain-regulated Estrogen Receptor α-mediated Control of Insulin-like Growth Factor (IGF) I Receptor Sensitivity to Ambient IGF, Leading to Phosphatidylinositol 3-Kinase/AKT-dependent Wnt/LRP5 Receptor-independent Activation of β-Catenin Signaling , 2009, The Journal of Biological Chemistry.

[28]  A. Bradford,et al.  Protein kinase C alpha‐dependent signaling mediates endometrial cancer cell growth and tumorigenesis , 2009, International journal of cancer.

[29]  Xiaowei Wang,et al.  PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification , 2009, Nucleic Acids Res..

[30]  Guoyin Feng,et al.  Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[31]  C. Jacobs,et al.  Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro. , 2009, Bone.

[32]  Eun-Young Kim,et al.  Stimulation of protein kinase C‐α suppresses colon cancer cell proliferation by down‐regulation of β‐catenin , 2009 .

[33]  B. Frenkel,et al.  Lef1 Haploinsufficient Mice Display a Low Turnover and Low Bone Mass Phenotype in a Gender- and Age-Specific Manner , 2009, PloS one.

[34]  P. Verkade,et al.  PKCalpha regulates platelet granule secretion and thrombus formation in mice. , 2009, Journal of Clinical Investigation.

[35]  D. Amato,et al.  The clinical course of untreated Gaucher disease in 22 patients over 10 years: hematological and skeletal manifestations. , 2008, Blood cells, molecules & diseases.

[36]  W. Thomas,et al.  Membrane ERα-dependent activation of PKCα in endometrial cancer cells by estradiol , 2008, Steroids.

[37]  Matthew R Allen,et al.  Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin* , 2008, Journal of Biological Chemistry.

[38]  C. O’Brien,et al.  A Novel Ligand-independent Function of the Estrogen Receptor Is Essential for Osteocyte and Osteoblast Mechanotransduction* , 2007, Journal of Biological Chemistry.

[39]  C. Chenu,et al.  Blockade of beta-adrenergic signaling does not influence the bone mechano-adaptive response in mice. , 2007, Bone.

[40]  L. Lanyon,et al.  Wnt/β-Catenin Signaling Is a Component of Osteoblastic Bone Cell Early Responses to Load-bearing and Requires Estrogen Receptor α* , 2007, Journal of Biological Chemistry.

[41]  A. Teti,et al.  Modulation of human estrogen receptor alpha F promoter by a protein kinase C/c-Src-dependent mechanism in osteoblast-like cells. , 2006, Journal of molecular endocrinology.

[42]  Eun-Young Kim,et al.  Protein-kinase-C-mediated β-catenin phosphorylation negatively regulates the Wnt/β-catenin pathway , 2006, Journal of Cell Science.

[43]  Mark L. Johnson,et al.  Wnt/β-Catenin Signaling Is a Normal Physiological Response to Mechanical Loading in Bone* , 2006, Journal of Biological Chemistry.

[44]  M. Leitges,et al.  Protein kinase c alpha but not PKC zeta suppresses intestinal tumor formation in Apc(Min/+) mice , 2006 .

[45]  T. Skerry,et al.  One mechanostat or many? Modifications of the site-specific response of bone to mechanical loading by nature and nurture. , 2006, Journal of musculoskeletal & neuronal interactions.

[46]  Janet L Stein,et al.  Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression* , 2005, Journal of Biological Chemistry.

[47]  Masaki Noda,et al.  Unloading Induces Osteoblastic Cell Suppression and Osteoclastic Cell Activation to Lead to Bone Loss via Sympathetic Nervous System* , 2005, Journal of Biological Chemistry.

[48]  S. Majumdar,et al.  Hyaluronan Increases RANKL Expression in Bone Marrow Stromal Cells Through CD44 , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[49]  S. Boonen,et al.  Androgens and bone. , 2004, Calcified tissue international.

[50]  T. Hewett,et al.  PKC-α regulates cardiac contractility and propensity toward heart failure , 2004, Nature Medicine.

[51]  L. Lanyon,et al.  Endocrinology: Bone adaptation requires oestrogen receptor-α , 2003, Nature.

[52]  L. Lanyon,et al.  Human Osteoblasts' Proliferative Responses to Strain and 17β‐Estradiol Are Mediated by the Estrogen Receptor and the Receptor for Insulin‐Like Growth Factor I , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[53]  S. Ohno,et al.  Regulation of expression and activity of four PKC isozymes in confluent and mechanically stimulated UMR‐108 osteoblastic cells , 2001, Journal of cellular physiology.

[54]  L. Lanyon,et al.  Perspective: Postmenopausal Osteoporosis as a Failure of Bone's Adaptation to Functional Loading: A Hypothesis * , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[55]  J M Polak,et al.  Mechanical Strain Stimulates Nitric Oxide Production by Rapid Activation of Endothelial Nitric Oxide Synthase in Osteocytes , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[56]  D. Elstein,et al.  Platelet function abnormalities in Gaucher disease patients , 1999, American journal of hematology.

[57]  I. Owan,et al.  Recruitment and proliferative responses of osteoblasts after mechanical loading in vivo determined using sustained-release bromodeoxyuridine. , 1998, Bone.

[58]  T. Thorsen,et al.  Modulation of mouse estrogen receptor transcription activity by protein kinase C delta. , 1998, Journal of molecular endocrinology.

[59]  L. Lanyon,et al.  Calvarial and limb bone cells in organ and monolayer culture do not show the same early responses to dynamic mechanical strain , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[60]  W. Wetsel,et al.  Endogenous protein kinase-C activation in osteoblast-like cells modulates responsiveness to estrogen and estrogen receptor levels. , 1993, Molecular endocrinology.

[61]  J. Dambrosia,et al.  Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. , 1991, The New England journal of medicine.

[62]  L E Lanyon,et al.  Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading , 1988, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[63]  Y. Hannun,et al.  Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. , 1987, Science.

[64]  Z. Jaworski,et al.  Bone loss in response to long-term immobilisation. , 1978, The Journal of bone and joint surgery. British volume.

[65]  Matthew R Allen,et al.  Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. , 2012, Bone.

[66]  W. Wetsel,et al.  Interaction of estrogen receptor alpha with protein kinase C alpha and c-Src in osteoblasts during differentiation. , 2004, Bone.

[67]  R. Suswillo,et al.  The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor- (cid:1) and - (cid:2) , 2004 .

[68]  B. Bembi,et al.  Skeletal aspects of Gaucher disease: a review. , 2002, The British journal of radiology.