Osteocyte: the unrecognized side of bone tissue

IntroductionOsteocytes represent 95% of all bone cells. These cells are old osteoblasts that occupy the lacunar space and are surrounded by the bone matrix. They possess cytoplasmic dendrites that form a canalicular network for communication between osteocytes and the bone surface. They express some biomarkers (osteopontin, β3 integrin, CD44, dentin matrix protein 1, sclerostin, phosphate-regulating gene with homologies to endopeptidases on the X chromosome, matrix extracellular phosphoglycoprotein, or E11/gp38) and have a mechano-sensing role that is dependent upon the frequency, intensity, and duration of strain.DiscussionThe mechanical information transmitted into the cytoplasm also triggers a biological cascade, starting with NO and PGE2 and followed by Wnt/β catenin signaling. This information is transmitted to the bone surface through the canalicular network, particularly to the lining cells, and is able to trigger bone remodeling by directing the osteoblast activity and the osteoclastic resorption. Furthermore, the osteocyte death seems to play also an important role. The outcome of micro-cracks in the vicinity of osteocytes may interrupt the canalicular network and trigger cell apoptosis in the immediate surrounding environment. This apoptosis appears to transmit a message to the bone surface and activate remodeling. The osteocyte network also plays a recognized endocrine role, particularly concerning phosphate regulation and vitamin D metabolism. Both the suppression of estrogen following menopause and chronic use of systemic glucocorticoids induce osteocyte apoptosis. On the other hand, physical activity has a positive impact in the reduction of apoptosis. In addition, some osteocyte molecular elements like sclerostin, connexin 43, E11/gp38, and DKK1 are emerging as promising targets for the treatment of various osteo-articular pathologies.

[1]  L. Bonewald,et al.  Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. , 2005, Molecular biology of the cell.

[2]  S. Cowin,et al.  Ultrastructure of the osteocyte process and its pericellular matrix. , 2004, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[3]  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.

[4]  B. Clarke,et al.  Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism , 2008 .

[5]  C. Tei,et al.  Oncogenic osteomalacia in a case with a maxillary sinus mesenchymal tumor. , 2006, The American journal of the medical sciences.

[6]  J. Currey The many adaptations of bone. , 2003, Journal of biomechanics.

[7]  T. Smit,et al.  Osteocyte morphology in fibula and calvaria --- is there a role for mechanosensing? , 2008, Bone.

[8]  J. Chow,et al.  Osteocytic expression of mRNA for c-fos and IGF-I: an immediate early gene response to an osteogenic stimulus. , 1996, The American journal of physiology.

[9]  S. Manolagas,et al.  Transduction of Cell Survival Signals by Connexin-43 Hemichannels* , 2002, The Journal of Biological Chemistry.

[10]  N. Itoh,et al.  Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. , 2000, Biochemical and biophysical research communications.

[11]  Animesh Nandi,et al.  Suppression of Aging in Mice by the Hormone Klotho , 2005, Science.

[12]  S. Goldstein,et al.  Microdamage Repair and Remodeling Requires Mechanical Loading , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[13]  T. Bellido Downregulation of SOST/sclerostin by PTH: a novel mechanism of hormonal control of bone formation mediated by osteocytes. , 2006, Journal of musculoskeletal & neuronal interactions.

[14]  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.

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

[16]  A. Ermolao,et al.  Short-term adapted physical activity program improves bone quality in osteopenic/osteoporotic postmenopausal women. , 2008, Journal of physical activity & health.

[17]  M. McKee,et al.  Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. , 2005, Genes & development.

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

[19]  M. Razzaque,et al.  Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. , 2004, Matrix biology : journal of the International Society for Matrix Biology.

[20]  K. Fukuda,et al.  Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. , 2003, Molecular endocrinology.

[21]  J. Reeve,et al.  The FASEB Journal express article 10.1096/fj.05-4221fje. Published online August 25, 2005. ©2005 FASEB , 2022 .

[22]  R. Reilly,et al.  Hypophosphatemia: an evidence-based approach to its clinical consequences and management , 2006, Nature Clinical Practice Nephrology.

[23]  Y. Nakahara,et al.  Associations of daily walking steps with calcaneal ultrasound parameters and a bone resorption marker in elderly Japanese women. , 2008, Journal of physiological anthropology.

[24]  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.

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

[26]  M. Kasper,et al.  Immunohistochemical investigations on the differentiation marker protein E11 in rat calvaria, calvaria cell culture and the osteoblastic cell line ROS 17/2.8 , 1999, Histochemistry and Cell Biology.

[27]  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.

[28]  L. Bélanger,et al.  The life cycle of the osteocyte. , 1973, Clinical orthopaedics and related research.

[29]  T. Clemens,et al.  Selected Contribution: Osteocytes upregulate HIF-1alpha in response to acute disuse and oxygen deprivation. , 2001, Journal of applied physiology.

[30]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  T. Hentunen,et al.  Conditioned medium from osteocytes stimulates the proliferation of bone marrow mesenchymal stem cells and their differentiation into osteoblasts. , 2004, Experimental cell research.

[32]  Jiliang Li,et al.  Risedronate and alendronate suppress osteocyte apoptosis following cyclic fatigue loading. , 2007, Bone.

[33]  S. Weinbaum,et al.  Strain amplification and integrin based signaling in osteocytes. , 2008, Journal of musculoskeletal & neuronal interactions.

[34]  R. Baron,et al.  Deletion of a Single Allele of the Dkk1 Gene Leads to an Increase in Bone Formation and Bone Mass , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

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

[36]  P. Kostenuik,et al.  Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[37]  Qing Chen,et al.  Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  T. Gross,et al.  Osteocyte hypoxia: a novel mechanotransduction pathway. , 1999, American journal of physiology. Cell physiology.

[39]  R. Rivera-Gonzalez,et al.  Identification of Osteoblast/Osteocyte Factor 45 (OF45), a Bone-specific cDNA Encoding an RGD-containing Protein That Is Highly Expressed in Osteoblasts and Osteocytes* , 2000, The Journal of Biological Chemistry.

[40]  R. Civitelli Connexin43 Modulation of Osteoblast/Osteocyte Apoptosis: A Potential Therapeutic Target? , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  B. Lanske,et al.  Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes. , 1996, Bone.

[42]  R. Robinson,et al.  CHANGES IN THE FINE STRUCTURE OF BONE CELLS AFTER THE ADMINISTRATION OF PARATHYROID EXTRACT , 1967, The Journal of cell biology.

[43]  Y. Nabeshima,et al.  The discovery of α-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis , 2008, Cellular and Molecular Life Sciences.

[44]  R. L. Cain,et al.  Catabolic effects of continuous human PTH (1--38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. , 2001, Endocrinology.

[45]  R. Weinstein,et al.  Connexin 43 Is Required for the Anti‐Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[46]  Y. Nabeshima [Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]. , 2008, Clinical calcium.

[47]  E. Bonucci,et al.  Effects of intermittent parathyroid hormone (PTH) administration on SOST mRNA and protein in rat bone , 2007, Journal of Molecular Histology.

[48]  C A Baud,et al.  Submicroscopic structure and functional aspects of the osteocyte. , 1968, Clinical orthopaedics and related research.

[49]  J. Weisel,et al.  Endocrine functions of bone in mineral metabolism regulation. , 2008, The Journal of clinical investigation.

[50]  S. Sokol,et al.  Regulation of Wnt/LRP Signaling by Distinct Domains of Dickkopf Proteins , 2002, Molecular and Cellular Biology.

[51]  Y. Mikuni‐Takagaki,et al.  Distinct responses of different populations of bone cells to mechanical stress. , 1996, Endocrinology.

[52]  E. Bonucci,et al.  OPG and RANKL mRNA and protein expressions in the primary and secondary metaphyseal trabecular bone of PTH-treated rats are independent of that of SOST , 2008, Journal of Molecular Histology.

[53]  C. Hartmann A Wnt canon orchestrating osteoblastogenesis. , 2006, Trends in cell biology.

[54]  B. Komm,et al.  Wnt signaling and osteoblastogenesis , 2007, Reviews in Endocrine and Metabolic Disorders.

[55]  F. Bronner Bone and calcium homeostasis. , 1992, Neurotoxicology.

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

[57]  R. Weinstein,et al.  Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. , 2000, The Journal of clinical endocrinology and metabolism.

[58]  T. Komori,et al.  Dentin Matrix Protein 1 Is Predominantly Expressed in Chicken and Rat Osteocytes But Not in Osteoblasts , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[59]  A. Ortiz Hutchinson-Gilford progeria syndrome. , 2008, The New England journal of medicine.

[60]  Anna Teti,et al.  Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. , 2009, Bone.

[61]  Toshitaka Nakamura,et al.  Changes in biological activity of bone cells in ovariectomized rats revealed by in situ hybridization , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[62]  K. Okawa,et al.  Klotho converts canonical FGF receptor into a specific receptor for FGF23 , 2006, Nature.

[63]  L. Bonewald Osteocytes as Dynamic Multifunctional Cells , 2007, Annals of the New York Academy of Sciences.

[64]  L. Ferrucci,et al.  Hutchinson-Gilford progeria syndrome. , 2008, The New England journal of medicine.

[65]  N. Fedarko,et al.  Six Genes Expressed in Bones and Teeth Encode the Current Members of the SIBLING Family of Proteins , 2003, Connective tissue research.

[66]  E H Burger,et al.  Pulsating Fluid Flow Stimulates Prostaglandin Release and Inducible Prostaglandin G/H Synthase mRNA Expression in Primary Mouse Bone Cells , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[67]  J. Aubin,et al.  Monoclonal antibodies as tools for studying the osteoblast lineage , 1996, Microscopy research and technique.

[68]  J. Heersche,et al.  Effects of hind limb unloading and reloading on nitric oxide synthase expression and apoptosis of osteocytes and chondrocytes. , 2006, Bone.

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

[70]  K. Nose,et al.  Isolation of a gene sequence induced later by tumor-promoting 12-O-tetradecanoylphorbol-13-acetate in mouse osteoblastic cells (MC3T3-E1) and expressed constitutively in ras-transformed cells. , 1990, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[71]  Theo H Smit,et al.  Osteocyte morphology in human tibiae of different bone pathologies with different bone mineral density--is there a role for mechanosensing? , 2009, Bone.

[72]  K. Rosenblatt,et al.  Regulation of Fibroblast Growth Factor-23 Signaling by Klotho* , 2006, Journal of Biological Chemistry.

[73]  D. Burr,et al.  Bone Microdamage and Skeletal Fragility in Osteoporotic and Stress Fractures , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[74]  H. Frost Bone dynamics in metabolic bone disease. , 1966, The Journal of bone and joint surgery. American volume.

[75]  E. Seeman,et al.  Osteocytes—martyrs for integrity of bone strength , 2006, Osteoporosis International.

[76]  P. Nijweide,et al.  Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts--correlation with prostaglandin upregulation. , 1995, Biochemical and biophysical research communications.

[77]  J. Westendorf,et al.  Wnt signaling in osteoblasts and bone diseases. , 2004, Gene.

[78]  O. Fromigué,et al.  Growth factors and bone formation in osteoporosis: roles for fibroblast growth factor and transforming growth factor beta. , 2004, Current pharmaceutical design.

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

[80]  P. ten Dijke,et al.  SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. , 2005, Cytokine & growth factor reviews.

[81]  J. Stains,et al.  Gap junctions regulate extracellular signal-regulated kinase signaling to affect gene transcription. , 2004, Molecular biology of the cell.

[82]  L. Gerstenfeld Osteopontin in Skeletal Tissue Homeostasis: An Emerging Picture of the Autocrine/Paracrine Functions of the Extracellular Matrix , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[83]  G. Marotti The structure of bone tissues and the cellular control of their deposition. , 1996, Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia.

[84]  R. Talmage,et al.  An interpretation of acute changes in plasma45Ca following parathyroid hormone administration to thyroparathyroidectomized rats , 1977, Calcified Tissue Research.

[85]  R. Thakker,et al.  Oncogenic hypophosphataemic osteomalacia: biomarker roles of fibroblast growth factor 23, 1,25-dihydroxyvitamin D3 and lymphatic vessel endothelial hyaluronan receptor 1. , 2008, European journal of endocrinology.

[86]  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.

[87]  Alexander G Robling,et al.  Improved Bone Structure and Strength After Long‐Term Mechanical Loading Is Greatest if Loading Is Separated Into Short Bouts , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[88]  L. Bonewald,et al.  Establishment of an Osteocyte‐like Cell Line, MLO‐Y4 , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[89]  G. Chertow,et al.  Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. , 2004, Journal of the American Society of Nephrology : JASN.

[90]  J. Stains,et al.  Gap junctions in skeletal development and function. , 2005, Biochimica et biophysica acta.

[91]  Jian Q. Feng,et al.  Pathogenic role of Fgf23 in Dmp1-null mice. , 2008, American journal of physiology. Endocrinology and metabolism.

[92]  B. Noble,et al.  The osteocyte lineage. , 2008, Archives of biochemistry and biophysics.

[93]  L E Lanyon,et al.  Loading‐related increases in prostaglandin production in cores of adult canine cancellous bone in vitro: A role for prostacyclin in adaptive bone remodeling? , 1991, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[94]  K. Lindpaintner,et al.  Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease , 2002, Journal of medical genetics.

[95]  M. Horton,et al.  Adhesive properties of isolated chick osteocytes in vitro. , 1996, Bone.

[96]  M. McKee,et al.  Partial rescue of the Hyp phenotype by osteoblast-targeted PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) expression. , 2002, Molecular endocrinology.

[97]  Y. Mikuni‐Takagaki,et al.  Mechanotransduction in stretched osteocytes--temporal expression of immediate early and other genes. , 1998, Biochemical and biophysical research communications.

[98]  N Loveridge,et al.  Identification of apoptotic changes in osteocytes in normal and pathological human bone. , 1997, Bone.

[99]  M. Kneissel,et al.  SOST is a target gene for PTH in bone. , 2005, Bone.

[100]  A. Robling,et al.  Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. , 2006, Journal of musculoskeletal & neuronal interactions.

[101]  R Huiskes,et al.  Osteocyte density changes in aging and osteoporosis. , 1996, Bone.

[102]  H. Ozawa,et al.  Osteocytic osteolysis observed in rats to which parathyroid hormone was continuously administered , 2004, Journal of Bone and Mineral Metabolism.

[103]  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.

[104]  M Dioszegi,et al.  Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). , 2001, Human molecular genetics.

[105]  S. Manolagas,et al.  Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. , 2000, Endocrine reviews.

[106]  S. Itohara,et al.  A Crucial Role for Matrix Metalloproteinase 2 in Osteocytic Canalicular Formation and Bone Metabolism* , 2006, Journal of Biological Chemistry.

[107]  Lijun Liu,et al.  Beta-subunit of cardiac Na+-K+-ATPase dictates the concentration of the functional enzyme in caveolae. , 2006, American journal of physiology. Cell physiology.

[108]  Shigeo M. Tanaka,et al.  Knee loading stimulates cortical bone formation in murine femurs , 2006, BMC musculoskeletal disorders.

[109]  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.

[110]  Jianhua Ruan,et al.  A systems biology approach to the identification and analysis of transcriptional regulatory networks in osteocytes , 2009, BMC Bioinformatics.

[111]  G. Roth,et al.  Parathyroid hormone stimulates phosphate efflux through an apparently adenosine 3',5'-monophosphate-independent process in rat parotid cell aggregates. , 1986, Endocrinology.

[112]  D. Zaffe,et al.  Osteocyte differentiation in the tibia of newborn rabbit: an ultrastructural study of the formation of cytoplasmic processes. , 1990, Acta anatomica.

[113]  D. Paul,et al.  Connexins, connexons, and intercellular communication. , 1996, Annual review of biochemistry.

[114]  W. Reinus,et al.  Juvenile paget disease: Life‐long features of a mildly affected young woman , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[115]  L. Bonewald,et al.  Mechanosensation and Transduction in Osteocytes. , 2006, BoneKEy osteovision.

[116]  P. Marie,et al.  New factors controlling bone remodeling. , 2000, Joint, bone, spine : revue du rhumatisme.

[117]  Di Chen,et al.  MEPE has the properties of an osteoblastic phosphatonin and minhibin. , 2004, Bone.

[118]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[119]  J. Wit,et al.  The Role of Estrogen in the Control of Rat Osteocyte Apoptosis , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[120]  John A Latham,et al.  Osteocyte control of bone formation via sclerostin, a novel BMP antagonist , 2003, The EMBO journal.

[121]  S. Donahue,et al.  Mechanical stimulation of MC3T3 osteoblastic cells in a bone tissue-engineering bioreactor enhances prostaglandin E2 release. , 2005, Tissue engineering.

[122]  Mark L. Johnson,et al.  Osteocytes, mechanosensing and Wnt signaling. , 2008, Bone.

[123]  J. Wergedal,et al.  Bone formation by osteocytes. , 1971, The American journal of physiology.

[124]  E. Schneider,et al.  The potential of gene therapy for fracture healing in osteoporosis , 2005, Osteoporosis International.

[125]  L. Bonewald,et al.  Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading* , 2008, Journal of Biological Chemistry.

[126]  S. Manolagas Choreography from the tomb: An emerging role of dying osteocytes in the purposeful, and perhaps not so purposeful, targeting of bone remodeling , 2006 .

[127]  J. Stock,et al.  Targeted Disruption of the Osteoblast/Osteocyte Factor 45 Gene (OF45) Results in Increased Bone Formation and Bone Mass* , 2003, The Journal of Biological Chemistry.

[128]  Talmage Rv,et al.  Calcium homeostasis: how bone solubility relates to all aspects of bone physiology. , 2007 .

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

[130]  N. Itoh,et al.  Evolution of the Fgf and Fgfr gene families. , 2004, Trends in genetics : TIG.

[131]  A. Hand,et al.  Immunogold localization of beta 1-integrin in bone: effect of glucocorticoids and insulin-like growth factor I on integrins and osteocyte formation. , 1995, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[132]  Jonathan Reeve,et al.  Osteocyte function, osteocyte death and bone fracture resistance , 2000, Molecular and Cellular Endocrinology.

[133]  S C Cowin,et al.  Mechanosensation and fluid transport in living bone. , 2002, Journal of musculoskeletal & neuronal interactions.

[134]  M. Gardner,et al.  The aging spine: new technologies and therapeutics for the osteoporotic spine , 2003, European Spine Journal.

[135]  Masaki Hojo,et al.  Calcium response in single osteocytes to locally applied mechanical stimulus: differences in cell process and cell body. , 2009, Journal of biomechanics.

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

[137]  M. Yeager,et al.  Three-dimensional structure of a recombinant gap junction membrane channel. , 1999, Science.

[138]  L. Selvaggi,et al.  Effect of oestrogen replacement on bone metabolism and cytokines in surgical menopause , 1995, Clinical Rheumatology.

[139]  P. Roberson,et al.  Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. , 1999, The Journal of clinical investigation.

[140]  D. Galas,et al.  A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. , 2002, American journal of medical genetics.

[141]  Clinton T. Rubin,et al.  Skeletal strain and the functional significance of bone architecture , 2006, Calcified Tissue International.

[142]  G. Marotti,et al.  Structure and function of lamellar bone. , 1994, Clinical rheumatology.

[143]  J. Heersche,et al.  Lifetime of the osteoblast in mouse periodontium , 1988, The Anatomical record.