Mechanosensation and Transduction in Osteocytes.

There may be no single mechanoreceptor in osteocytes, but instead a combination of events that has to be triggered for mechanosensation and transduction of signal to occur. Possibilities include shear stress along dendritic processes and/or the cell body, cell deformation in response to strain, and primary cilia. These events could occur independently or simultaneously to activate mechanotransduction. Signal initiators include calcium channel activation and ATP, nitric oxide, and prostaglandin release. Means of signal transfer include gap junctions and hemichannels, and the release of signaling molecules into the bone fluid. Questions remain regarding the magnitude of strain necessary to induce an osteocyte response, how the response propagates within the osteocyte network, and the timing involved in the initiation of bone resorption and/or formation on the bone surface. Mechanical loading in the form of shear stress is clearly involved not only in mechanosensation and transduction, but also in osteocyte viability. It remains to be determined if mechanical loading can also affect mineral homeostasis and mineralization, which are newly recognized functions of osteocytes.

[1]  E H Burger,et al.  The production of nitric oxide and prostaglandin E(2) by primary bone cells is shear stress dependent. , 2001, Journal of biomechanics.

[2]  J. Reeve,et al.  Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  M. Forwood,et al.  Inducible cyclo‐oxygenase (COX‐2) mediates the induction of bone formation by mechanical loading in vivo , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  L. Bonewald,et al.  Mechanism by which MLO-A5 Late Osteoblasts/Early Osteocytes Mineralize in Culture: Similarities with Mineralization of Lamellar Bone , 2006, Calcified Tissue International.

[5]  S. Cowin,et al.  Candidates for the mechanosensory system in bone. , 1991, Journal of biomechanical engineering.

[6]  D. Burr,et al.  Partitioning a Daily Mechanical Stimulus into Discrete Loading Bouts Improves the Osteogenic Response to Loading , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[7]  T. Takano-Yamamoto,et al.  A three-dimensional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy. , 2001, Bone.

[8]  M. Karperien,et al.  Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist , 2004, The Journal of experimental medicine.

[9]  D. Burr,et al.  Effects of biomechanical stress on bones in animals. , 2002, Bone.

[10]  L. Bonewald,et al.  Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism , 2006, Nature Genetics.

[11]  F. Giancotti,et al.  Complexity and specificity of integrin signalling , 2000, Nature Cell Biology.

[12]  Jacques P. Brown,et al.  Sequestosome 1: Mutation Frequencies, Haplotypes, and Phenotypes in Familial Paget's Disease of Bone , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[13]  L. Bonewald,et al.  MLO‐Y4 Osteocyte‐Like Cells Support Osteoclast Formation and Activation , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[14]  T. Meitinger,et al.  Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia. , 1997, Human molecular genetics.

[15]  R. Recker,et al.  Bone biomechanical properties in LRP5 mutant mice. , 2004, Bone.

[16]  Y. Yamaguchi,et al.  Isolated chick osteocytes stimulate formation and bone-resorbing activity of osteoclast-like cells , 2005, Journal of Bone and Mineral Metabolism.

[17]  Stephen E. Harris,et al.  E11/gp38 Selective Expression in Osteocytes: Regulation by Mechanical Strain and Role in Dendrite Elongation , 2006, Molecular and Cellular Biology.

[18]  Xi Jiang,et al.  Pathogenic role of Fgf 23 in Hyp mice , 2006 .

[19]  L. Lanyon Osteocytes, strain detection, bone modeling and remodeling , 2005, Calcified Tissue International.

[20]  A. Parfitt,et al.  Osteocyte Apoptosis Is Induced by Weightlessness in Mice and Precedes Osteoclast Recruitment and Bone Loss , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  L. Bonewald,et al.  Mechanical Loading Stimulates Dentin Matrix Protein 1 (DMP1) Expression in Osteocytes In Vivo , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  P. Selby Guidelines for the Diagnosis and Management of Paget's Disease: A UK Perspective , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[23]  L. Lanyon,et al.  The Effect of In Vivo Mechanical Loading on Estrogen Receptor α Expression in Rat Ulnar Osteocytes , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[24]  M. Balooch,et al.  Glucocorticoid‐Treated Mice Have Localized Changes in Trabecular Bone Material Properties and Osteocyte Lacunar Size That Are Not Observed in Placebo‐Treated or Estrogen‐Deficient Mice , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[25]  J. Robb,et al.  Electrophysiological Responses of Human Bone Cells to Mechanical Stimulation: Evidence for Specific Integrin Function in Mechanotransduction , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  L. Lanyon,et al.  Regulation of bone formation by applied dynamic loads. , 1984, The Journal of bone and joint surgery. American volume.

[27]  E H Burger,et al.  Signal transduction pathways involved in fluid flow-induced PGE2 production by cultured osteocytes. , 1999, American journal of physiology. Endocrinology and metabolism.

[28]  Alexander G Robling,et al.  Shorter, more frequent mechanical loading sessions enhance bone mass. , 2002, Medicine and science in sports and exercise.

[29]  M W Otter,et al.  Mechanotransduction in bone: do bone cells act as sensors of fluid flow? , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  Xi Jiang,et al.  Pathogenic role of Fgf23 in Hyp mice. , 2006, American journal of physiology. Endocrinology and metabolism.

[31]  A. Parfitt,et al.  The cellular basis of bone turnover and bone loss: a rebuttal of the osteocytic resorption--bone flow theory. , 1977, Clinical orthopaedics and related research.

[32]  Daniel P Nicolella,et al.  Osteocyte lacunae tissue strain in cortical bone. , 2006, Journal of biomechanics.

[33]  Shiqin Zhang,et al.  Cilia-like Structures and Polycystin-1 in Osteoblasts/Osteocytes and Associated Abnormalities in Skeletogenesis and Runx2 Expression* , 2006, Journal of Biological Chemistry.

[34]  Daniel P Nicolella,et al.  Measurement of microstructural strain in cortical bone. , 2005, European journal of morphology.

[35]  Olivier Verborgt,et al.  Spatial Distribution of Bax and Bcl‐2 in Osteocytes After Bone Fatigue: Complementary Roles in Bone Remodeling Regulation? , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  Peng Liu,et al.  Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling* , 2005, Journal of Biological Chemistry.

[37]  B. Hall,et al.  Buried alive: How osteoblasts become osteocytes , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[38]  Jenneke Klein-Nulend,et al.  Shear stress inhibits while disuse promotes osteocyte apoptosis. , 2004, Biochemical and biophysical research communications.

[39]  K. White,et al.  MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. , 2000, Genomics.

[40]  L. Lanyon,et al.  Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. , 2003, American journal of physiology. Cell physiology.

[41]  Mark L. Johnson,et al.  The gene for high bone mass , 2002 .

[42]  S. Cowin,et al.  A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. , 1994, Journal of biomechanics.

[43]  R. Recker,et al.  Mechanical loading stimulates rapid changes in periosteal gene expression , 1994, Calcified Tissue International.

[44]  H. Hagino,et al.  Effect of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the cortical bone response to mechanical loading. , 2005, Bone.

[45]  A. Robling,et al.  The Wnt Co-receptor LRP5 Is Essential for Skeletal Mechanotransduction but Not for the Anabolic Bone Response to Parathyroid Hormone Treatment* , 2006, Journal of Biological Chemistry.

[46]  A. Parfitt,et al.  Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs. , 2005, American journal of physiology. Cell physiology.

[47]  J. Frangos,et al.  Bone cell responses to fluid flow. , 2003, Methods in molecular medicine.

[48]  Sheldon Weinbaum,et al.  In situ measurement of solute transport in the bone lacunar‐canalicular system , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Sheldon Weinbaum,et al.  Mechanotransduction and strain amplification in osteocyte cell processes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[51]  L. Bonewald,et al.  Dentin Matrix Protein 1 Gene Cis-regulation , 2005, Journal of Biological Chemistry.

[52]  D. Burr,et al.  A Model for mechanotransduction in bone cells: The load‐bearing mechanosomes , 2003, Journal of cellular biochemistry.

[53]  L. Lanyon,et al.  Early strain‐related changes in enzyme activity in osteocytes following bone loading in vivo , 1989, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[54]  J. Reiter,et al.  The Primary Cilium as the Cell's Antenna: Signaling at a Sensory Organelle , 2006, Science.