Bone cell senescence: Mechanisms and perspectives

Journal of Bone and Mineral Research

Volumn 29, Issue 6, 2014, Pages 1311-1321

  Marie, Pierre J ^a,b  

^a HÔPITAL LARIBOISIÈRE   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

Author keywords

AGING; AUTOPHAGY; CELL CELL COMMUNICATIONS; EPIGENETICS; LOCAL FACTORS; NICHES; PROTEASOME; SENESCENCE

Indexed keywords

DNA; PROTEASOME;

AUTOPHAGY; BONE CELL; CELL AGING; CELL COMMUNICATION; CELL DAMAGE; CELL DIFFERENTIATION; CELL FUNCTION; DNA REPAIR; ENZYME DEGRADATION; EPIGENETICS; GENETIC TRANSCRIPTION; HUMAN; MICROENVIRONMENT; NONHUMAN; OXIDATIVE STRESS; REVIEW; SENESCENCE; SKELETON; TELOMERE SHORTENING; AGING; BONE; CYTOLOGY; PHYSIOLOGY; TUMOR MICROENVIRONMENT;

AGING; BONE AND BONES; CELL AGING; CELLULAR MICROENVIRONMENT; HUMANS;

EID: 84901254305     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.2190     Document Type: Review

References (182)

1. Jasper H, Kennedy BK., Niche science: the aging stem cell. Cell Cycle. 2012; 11: 2959-60.
2. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G., The hallmarks of aging. Cell. 2013; 153: 1194-217.
3. Khosla S, Bellido TM, Drezner MK, et al. Forum on aging and skeletal health: summary of the proceedings of an ASBMR workshop. J Bone Miner Res. 2011; 26: 2565-78.
4. Manolagas SC, Parfitt AM., What old means to bone. Trends Endocrinol Metab. 2010; 21 (6): 369-74.
5. Boskey AL, Coleman R., Aging and bone. J Dent Res. 2010; 89: 1333-48.
6. Freund A, Orjalo AV, Desprez PY, Campisi J., Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010; 16: 238-46.
7. Kassem M, Marie PJ., Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell. 2011; 10 (2): 191-7.
8. Marie PJ, Kassem M., Extrinsic mechanisms involved in age-related defective bone formation. J Clin Endocrinol Metab. 2011; 96: 600-9.
9. Marie PJ, Kassem M., Osteoblasts in osteoporosis: past, emerging and future anabolic targets. Eur J Endocrinol. 2011; 165 (1): 1-10.
10. de Lange T., Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005; 19: 2100-10.
11. Nandakumar J, Cech TR., Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol. 2013; 14: 69-82.
12. Campisi J, Kim SH, Lim CS, Rubio M., Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol. 2001; 36: 1619-37.
13. Pignolo RJ, Suda RK, McMillan EA, et al. Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Aging Cell. 2008; 7: 23-31.
14. Saeed H, Abdallah BM, Ditzel N, et al. Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment. J Bone Miner Res. 2011; 26: 1494-505.
15. Wang H, Chen Q, Lee SH, Choi Y, Johnson FB, Pignolo RJ., Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell. 2012; 11: 704-13.
16. Yudoh K, Matsuno H, Nakazawa F, Katayama R, Kimura T., Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts. J Bone Miner Res. 2001; 16: 1453-64.
17. Gronthos S, Chen S, Wang CY, Robey PG, Shi S., Telomerase accelerates osteogenesis of bone marrow stromal stem cells by upregulation of CBFA1, osterix, and osteocalcin. J Bone Miner Res. 2003; 18: 716-22.
18. Yudoh K, Nishioka K., Telomerized presenescent osteoblasts prevent bone mass loss in vivo. Gene Ther. 2004; 11: 909-15.
19. Shi S, Gronthos S, Chen S, et al. Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nat Biotechnol. 2002; 20: 587-91.
20. Simonsen JL, Rosada C, Serakinci N, et al. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol. 2002; 20: 592-6.
21. Bernardes de Jesus B, Vera E, Schneeberger K, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012; 4: 691-704.
22. Manolagas SC., Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000; 21: 115-37.
23. Manolagas SC, Almeida M., Gone with the Wnts: beta-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol. 2007; 21: 2605-14.
24. Gambino V, De Michele G, Venezia O, et al. Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging. Aging Cell. 2013; 12: 435-45.
25. Almeida M., Aging mechanisms in bone. Bonekey Rep. 2012; 1: 102.
26. Nojiri H, Saita Y, Morikawa D, et al. Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J Bone Miner Res. 2011; 26: 2682-94.
27. Morikawa D, Nojiri H, Saita Y, et al. Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. J Bone Miner Res. 2013; 28: 2368-80.
28. Kawai M, de Paula FJ, Rosen CJ., New insights into osteoporosis: the bone-fat connection. J Intern Med. 2012; 272: 317-29.
29. Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL., Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-gamma expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem. 2009; 284: 27438-48.
30. Weinstein RS, Wan C, Liu Q, et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell. 2010; 9: 147-61.
31. Rached MT, Kode A, Xu L, et al. FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab. 2010; 11: 147-60.
32. Almeida M, Han L, Martin-Millan M, O'Brien CA, Manolagas SC., Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem. 2007; 282: 27298-305.
33. Baron R, Kneissel M., WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013; 19: 179-92.
34. Iyer S, Ambrogini E, Bartell SM, et al. FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest. 2013; 123: 3409-19.
35. Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR., Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest. 1990; 85: 632-9.
36. Baek KH, Oh KW, Lee WY, et al. Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures. Calcif Tissue Int. 2010; 87: 226-35.
37. Boyce BF, Yao Z, Xing L., Functions of nuclear factor kappaB in bone. Ann NY Acad Sci. 2010; 1192: 367-75.
38. Krum SA, Chang J, Miranda-Carboni G, Wang CY., Novel functions for NFkappaB: inhibition of bone formation. Nat Rev Rheumatol. 2010; 6: 607-11.
39. Novack DV., Role of NF-kappaB in the skeleton. Cell Res. 2011; 21: 169-82.
40. Chen Q, Liu K, Robinson AR, et al. DNA damage drives accelerated bone aging via an NF-kappaB-dependent mechanism. J Bone Miner Res. 2013; 28: 1214-28.
41. Lean JM, Davies JT, Fuller K, et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest. 2003; 112: 915-23.
42. Jagger CJ, Lean JM, Davies JT, Chambers TJ., Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. Endocrinology. 2005; 146: 113-8.
43. Sun Y, Shuang F, Chen DM, Zhou RB., Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats. Osteoporos Int. 2013; 24: 969-78.
44. Jilka RL, Almeida M, Ambrogini E, et al. Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration. Aging Cell. 2010; 9: 851-67.
45. Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007; 282: 27285-97.
46. Yang S, Madyastha P, Bingel S, Ries W, Key L., A new superoxide- generating oxidase in murine osteoclasts. J Biol Chem. 2001; 276: 5452-8.
47. Goettsch C, Babelova A, Trummer O, et al. NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis. J Clin Invest. 2013; 123: 4731-8.
48. Fraga MF., Genetic and epigenetic regulation of aging. Curr Opin Immunol. 2009; 21: 446-53.
49. Munoz-Najar U, Sedivy JM., Epigenetic control of aging. Antioxid Redox Signal. 2011; 14: 241-59.
50. Delgado-Calle J, Sanudo C, Fernandez AF, Garcia-Renedo R, Fraga MF, Riancho JA., Role of DNA methylation in the regulation of the RANKL-OPG system in human bone. Epigenetics. 2012; 7: 83-91.
51. Villagra A, Gutierrez J, Paredes R, et al. Reduced CpG methylation is associated with transcriptional activation of the bone-specific rat osteocalcin gene in osteoblasts. J Cell Biochem. 2002; 85: 112-22.
52. Fu B, Wang H, Wang J, et al. Epigenetic regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA methylation and histone modification. PLoS One. 2013; 8: e61423.
53. Delgado-Calle J, Sanudo C, Bolado A, et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Miner Res. 2012; 27: 926-37.
54. Li J, Zhang N, Huang X, et al. Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation. Cell Death Dis. 2013; 4: e832.
55. Zhao QH, Wang SG, Liu SX, et al. PPARgamma forms a bridge between DNA methylation,histone acetylation at the C/EBPalpha gene promoter to regulate the balance between osteogenesis,adipogenesis of bone marrow stromal cells. FEBS.J. 2013; 280: 5801-14.
56. Yasui T, Hirose J, Tsutsumi S, Nakamura K, Aburatani H, Tanaka S., Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1. J Bone Miner Res. 2011; 26: 2665-71.
57. Wei Y, Chen YH, Li LY, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011; 13: 87-94.
58. Ye L, Fan Z, Yu B, et al. Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell. 2012; 11: 50-61.
59. Sinha KM, Yasuda H, Zhou X, Decrombrugghe B., Osterix and NO66 histone demethylase control the chromatin architecture of Osterix target genes during osteoblast differentiation. J Bone Miner Res. 2013 Sep 23. [Epub ahead of print]
60. Yang D, Okamura H, Nakashima Y, Haneji T., Histone demethylase Jmjd3 regulates osteoblast differentiation via transcription factors Runx2 and osterix. J Biol Chem. 2013; 288: 33530-41.
61. Takada I, Mihara M, Suzawa M, et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol. 2007; 9: 1273-85.
62. Bradley EW, McGee-Lawrence ME, Westendorf JJ., Hdac-mediated control of endochondral and intramembranous ossification. Crit Rev Eukaryot Gene Expr. 2011; 21: 101-13.
63. Dudakovic A, Evans JM, Li Y, Middha S, McGee-Lawrence ME, van Wijnen AJ, Westendorf JJ., Histone deacetylase inhibition promotes osteoblast maturation by altering the histone H4 epigenome and reduces Akt phosphorylation. J Biol Chem. 2013; 288: 28783-91.
64. Hesse E, Saito H, Kiviranta R, et al. Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity. J Cell Biol. 2010; 191: 1271-83.
65. Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z., Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun. 2013; 4: 1868.
66. Rodriguez RM, Fernandez AF, Fraga MF., Role of sirtuins in stem cell differentiation. Genes Cancer. 2013; 4: 105-11.
67. Guarente L., Sirtuins, aging, and metabolism. Cold Spring Harb Symp Quant Biol. 2011; 76: 81-90.
68. Cohen-Kfir E, Artsi H, Levin A, et al. Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor. Endocrinology. 2011; 152: 4514-24.
69. Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004; 429: 771-6.
70. Tseng PC, Hou SM, Chen RJ, et al. Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. J Bone Miner Res. 2011; 26: 2552-63.
71. Simic P, Zainabadi K, Bell E, et al. SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating beta-catenin. EMBO Mol Med. 2013; 5: 430-40.
72. Edwards JR, Perrien DS, Fleming N, et al. Silent information regulator (Sir)T1 inhibits NF-kappaB signaling to maintain normal skeletal remodeling. J Bone Miner Res. 2013; 28: 960-9.
73. Herranz D, Serrano M., SIRT1: recent lessons from mouse models. Nat Rev Cancer. 2010; 10: 819-23.
74. Jung HJ, Suh Y., MicroRNA in aging: from discovery to biology. Curr Genomics. 2012; 13: 548-57.
75. Dimmeler S, Nicotera P., MicroRNAs in age-related diseases. EMBO Mol Med. 2013; 5: 180-90.
76. van Wijnen AJ, van de Peppel J, van Leeuwen JP, et al. MicroRNA functions in osteogenesis and dysfunctions in osteoporosis. Curr Osteoporos Rep. 2013; 11: 72-82.
77. Lian JB, Stein GS, van Wijnen AJ, et al. MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol. 2012; 8: 212-27.
78. Rose L, Uludag H., Realizing the potential of gene-based molecular therapies in bone repair. J Bone Miner Res. 2013; 28: 2245-62.
79. Li H, Xie H, Liu W, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest. 2009; 119: 3666-77.
80. Wang FS, Chuang PC, Lin CL, et al. MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis Rheum. 2013; 65: 1530-40.
81. Zhang JF, Fu WM, He ML, et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell. 2011; 22: 3955-61.
82. Chen L, Holmstrom K, Qiu W, et al. MicroRNA-34a Inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. Stem Cells. 2014; 32: 902-12.
83. McGee-Lawrence ME, Bradley EW, Dudakovic A, et al. Histone deacetylase 3 is required for maintenance of bone mass during aging. Bone. 2013; 52: 296-307.
84. Backesjo CM, Li Y, Lindgren U, Haldosen LA., Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. J Bone Miner Res. 2006; 21: 993-1002.
85. Shakibaei M, Shayan P, Busch F, et al. Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation. PLoS One. 2012; 7: e35712.
86. Huang W, Shang WL, Wang HD, Wu WW, Hou SX., Sirt1 overexpression protects murine osteoblasts against TNF-alpha-induced injury in vitro by suppressing the NF-kappaB signaling pathway. Acta Pharmacol Sin. 2012; 33: 668-74.
87. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008; 8: 157-68.
88. Liu B, Ghosh S, Yang X, et al. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab. 2012; 16: 738-50.
89. Vessoni AT, Muotri AR, Okamoto OK., Autophagy in stem cell maintenance and differentiation. Stem Cells Dev. 2012; 21: 513-20.
90. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G., Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014; 15 (2): 81-94.
91. Young AR, Narita M., Connecting autophagy to senescence in pathophysiology. Curr Opin Cell Biol. 2010; 22: 234-40.
92. Hubbard VM, Valdor R, Macian F, Cuervo AM., Selective autophagy in the maintenance of cellular homeostasis in aging organisms. Biogerontology. 2012; 13: 21-35.
93. Boya P, Reggiori F, Codogno P., Emerging regulation and functions of autophagy. Nat Cell Biol. 2013; 15: 713-20.
94. Tezil T, Basaga H., Modulation of cell death in age-related diseases. Curr Pharm Des. 2013 Sep 27. [Epub ahead of print]
95. Shapiro IM, Layfield R, Lotz M, Settembre C, Whitehouse C., Boning up on autophagy: the role of autophagy in skeletal biology. Autophagy. 2014; 10: 7-19.
96. Hocking LJ, Whitehouse C, Helfrich MH., Autophagy: a new player in skeletal maintenance ? J Bone Miner Res. 2012; 27: 1439-47.
97. Wang K, Niu J, Kim H, Kolattukudy PE., Osteoclast precursor differentiation by MCPIP via oxidative stress, endoplasmic reticulum stress, and autophagy. J Mol Cell Biol. 2011; 3: 360-8.
98. DeSelm CJ, Miller BC, Zou W, et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell. 2011; 21: 966-74.
99. Liu F, Fang F, Yuan H, et al. Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J Bone Miner Res. 2013; 28: 2414-30.
100. Onal M, Piemontese M, Xiong J, et al. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem. 2013; 288: 17432-40.
101. Ciechanover A., Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture). Angew Chem Int Ed Engl. 2005; 44: 5944-67.
102. Dikic I, Wakatsuki S, Walters KJ., Ubiquitin-binding domains-from structures to functions. Nat Rev Mol Cell Biol. 2009; 10: 659-71.
103. Farout L, Friguet B., Proteasome function in aging and oxidative stress: implications in protein maintenance failure. Antioxid Redox Signal. 2006; 8: 205-16.
104. Grillari J, Katinger H, Voglauer R., Aging and the ubiquitinome: traditional and non-traditional functions of ubiquitin in aging cells and tissues. Exp Gerontol. 2006; 41: 1067-79.
105. Low P., The role of ubiquitin-proteasome system in ageing. Gen Comp Endocrinol. 2011; 172: 39-43.
106. Baraibar MA, Friguet B., Changes of the proteasomal system during the aging process. Prog Mol Biol Transl Sci. 2012; 109: 249-75.
107. Sévère N, Dieudonné FX, Marie PJ., E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis. Cell Death Dis. 2013; 4: e463.
108. Garrett IR, Chen D, Gutierrez G, et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest. 2003; 111: 1771-82.
109. Mukherjee S, Raje N, Schoonmaker JA, et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest. 2008; 118: 491-504.
110. Sévère N, Miraoui H, Marie PJ., The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011; 286: 24443-50.
111. Dieudonné FX, Sévère N, Biosse-Duplan M, Weng JJ, Su Y, Marie PJ., Promotion of osteoblast differentiation in mesenchymal cells through Cbl-mediated control of STAT5 activity. Stem Cells. 2013; 31: 1340-9.
112. Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B., Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell. 2004; 3: 379-89.
113. Xian L, Wu X, Pang L, et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med. 2012; 18: 1095-101.
114. Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ., Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012; 492: 1-18.
115. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis,bone mass by Wnt10b. Proc Natl Acad Sci USA. 2005; 102: 3324-9.
116. Rauner M, Sipos W, Pietschmann P., Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation. Age (Dordr). 2008; 30: 273-82.
117. Stevens JR, Miranda-Carboni GA, Singer MA, Brugger SM, Lyons KM, Lane TF., Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells. J Bone Miner Res. 2010; 25: 2138-47.
118. Florian MC, Nattamai KJ, Dorr K, et al. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature. 2013; 503: 392-6.
119. Fazeli PK, Horowitz MC, MacDougald OA, et al. Marrow fat and bone - new perspectives. J Clin Endocrinol Metab. 2013; 98: 935-45.
120. Ahdjoudj S, Fromigué O, Marie PJ., Plasticity and regulation of human bone marrow stromal osteoprogenitor cells: potential implication in the treatment of age-related bone loss. Histol Histopathol. 2004; 19: 151-7.
121. Berendsen AD, Olsen BR., Osteoblast-adipocyte lineage plasticity in tissue development, maintenance and pathology. Cell Mol Life Sci. 2014; 71: 493-7.
122. Nuttall ME, Shah F, Singh V, Thomas-Porch C, Frazier T, Gimble JM., Adipocytes and the regulation of bone remodeling: a balancing act. Calcif Tissue Int. 2014; 94: 78-87.
123. Lecka-Czernik B., PPARs and bone metabolism. PPAR Res. 2006; 2006: 18089.
124. Akune T, Ohba S, Kamekura S, et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004; 113: 846-55.
125. Gambardella A, Nagaraju CK, O'Shea PJ, et al. Glycogen synthase kinase-3alpha/beta inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage. J Bone Miner Res. 2011; 26: 811-21.
126. Duque G, Li W, Vidal C, Bermeo S, Rivas D, Henderson J., Pharmacological inhibition of PPARgamma increases osteoblastogenesis and bone mass in male C57BL/6 mice. J Bone Miner Res. 2013; 28: 639-48.
127. Vidal C, Bermeo S, Li W, Huang D, Kremer R, Duque G., Interferon gamma inhibits adipogenesis in vitro and prevents marrow fat infiltration in oophorectomized mice. Stem Cells. 2012; 30: 1042-8.
128. Menagh PJ, Turner RT, Jump DB, et al. Growth hormone regulates the balance between bone formation and bone marrow adiposity. J Bone Miner Res. 2010; 25: 757-68.
129. Rickard DJ, Wang FL, Rodriguez-Rojas AM, et al. Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells. Bone. 2006; 39: 1361-72.
130. Saidak Z, Haÿ E, Marty C, Barbara A, Marie PJ., Strontium ranelate rebalances bone marrow adipogenesis and osteoblastogenesis in senescent osteopenic mice through NFATc/Maf and Wnt signaling. Aging Cell. 2012; 11: 467-74.
131. Xiao L, Sobue T, Esliger A, et al. Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells. Bone. 2010; 47: 360-70.
132. Ahdjoudj S, Lasmoles F, Holy X, Zerath E, Marie PJ., Transforming growth factor beta2 inhibits adipocyte differentiation induced by skeletal unloading in rat bone marrow stroma. J Bone Miner Res. 2002; 17: 668-77.
133. Kang S, Bennett CN, Gerin I, Rapp LA, Hankenson KD, Macdougald OA., Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem. 2007; 282: 14515-24.
134. Song L, Liu M, Ono N, Bringhurst FR, Kronenberg HM, Guo J., Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. J Bone Miner Res. 2012; 27: 2344-58.
135. Liu Y, Berendsen AD, Jia S, et al. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest. 2012; 122: 3101-13.
136. Marie PJ, Kaabeche K., PPAR gamma activity and control of bone mass in skeletal unloading. PPAR Res. 2006; 2006: 64807.
137. David V, Martin A, Lafage-Proust MH, et al. Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis. Endocrinology. 2007; 148: 2553-62.
138. Sen B, Xie Z, Case N, et al. mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow derived mesenchymal stem cells. J Bone Miner Res. 2014; 29: 78-89.
139. van Bezooijen RL, Roelen BA, Visser A, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004; 199: 805-14.
140. Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011; 17: 1231-4.
141. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA., Matrix-embedded cells control osteoclast formation. Nat Med. 2011; 17: 1235-41.
142. Honma M, Ikebuchi Y, Kariya Y, et al. RANKL subcellular trafficking and regulatory mechanisms in osteocytes. J Bone Miner Res. 2013; 28: 1936-49.
143. Ozcivici E, Luu YK, Adler B, et al. Mechanical signals as anabolic agents in bone. Nat Rev Rheumatol. 2010; 6: 50-9.
144. Swift J, Ivanovska IL, Buxboim A, et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science. 2013; 341: 1240104.
145. Akter R, Rivas D, Geneau G, Drissi H, Duque G., Effect of lamin A/C knockdown on osteoblast differentiation and function. J Bone Miner Res. 2009; 24: 283-93.
146. Rauner M, Sipos W, Goettsch C, et al. Inhibition of lamin A/C attenuates osteoblast differentiation and enhances RANKL-dependent osteoclastogenesis. J Bone Miner Res. 2009; 24: 78-86.
147. Li W, Yeo LS, Vidal C, et al. Decreased bone formation and osteopenia in lamin a/c-deficient mice. PLoS One. 2011; 6: e19313.
148. Tong J, Li W, Vidal C, Yeo LS, Fatkin D, Duque G., Lamin A/C deficiency is associated with fat infiltration of muscle and bone. Mech Ageing Dev. 2011; 132: 552-9.
149. Rossi DJ, Jamieson CH, Weissman IL., Stems cells and the pathways to aging and cancer. Cell. 2008; 132: 681-96.
150. Haylock DN, Williams B, Johnston HM, et al. Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum. Stem Cells. 2007; 25: 1062-9.
151. Kohler A, Schmithorst V, Filippi MD, et al. Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones. Blood. 2009; 114: 290-8.
152. Li Z, Zhou Z, Saunders MM, Donahue HJ., Modulation of connexin43 alters expression of osteoblastic differentiation markers. Am J Physiol Cell Physiol. 2006; 290: C1248-55.
153. Plotkin LI, Bellido T., Beyond gap junctions: Connexin43 and bone cell signaling. Bone. 2013; 52: 157-66.
154. Stains JP, Watkins MP, Grimston SK, Hebert C, Civitelli R., Molecular mechanisms of osteoblast/osteocyte regulation by connexin43. Calcif Tissue Int. 2014; 94: 55-67.
155. Lloyd SA, Lewis GS, Zhang Y, Paul EM, Donahue HJ., Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading. J Bone Miner Res. 2012; 27: 2359-72.
156. Zappitelli T, Chen F, Moreno L, et al. The G60S connexin 43 mutation activates the osteoblast lineage and results in a resorption-stimulating bone matrix and abrogation of old-age-related bone loss. J Bone Miner Res. 2013; 28: 2400-13.
157. Genetos DC, Zhou Z, Li Z, Donahue HJ., Age-related changes in gap junctional intercellular communication in osteoblastic cells. J Orthop Res. 2012; 30: 1979-84.
158. Loiselle AE, Paul EM, Lewis GS, Donahue HJ., Osteoblast and osteocyte-specific loss of Connexin43 results in delayed bone formation and healing during murine fracture healing. J Orthop Res. 2013; 31: 147-54.
159. Bivi N, Condon KW, Allen MR, et al. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res. 2012; 27: 374-89.
160. Kar R, Riquelme MA, Werner S, Jiang JX., Connexin 43 channels protect osteocytes against oxidative stress-induced cell death. J Bone Miner Res. 2013; 28: 1611-21.
161. Marie PJ., Targeting integrins to promote bone formation and repair. Nat Rev Endocrinol. 2013; 9: 288-95.
162. Batra N, Burra S, Siller-Jackson AJ, et al. Mechanical stress-activated integrin alpha5beta1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci USA. 2012; 109: 3359-64.
163. Marie PJ., Role of N-cadherin in bone formation. J Cell Physiol. 2002; 190: 297-305.
164. Mbalaviele G, Shin CS, Civitelli R., Cell-cell adhesion and signaling through cadherins: connecting bone cells in their microenvironment. J Bone Miner Res. 2006; 21: 1821-7.
165. Heuberger J, Birchmeier W., Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010; 2: a002915.
166. Haÿ E, Laplantine E, Geoffroy V, et al. N-cadherin interacts with axin and LRP5 to negatively regulate Wnt/beta-catenin signaling, osteoblast function, and bone formation. Mol Cell Biol. 2009; 29: 953-64.
167. Castro CH, Shin CS, Stains JP, et al. Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis. J Cell Sci. 2004; 117: 2853-64.
168. Voog J, Jones DL., Stem cells and the niche: a dynamic duo. Cell Stem Cell. 2010; 6: 103-15.
169. Hoggatt J, Scadden DT., The stem cell niche: tissue physiology at a single cell level. J Clin Invest. 2012; 122: 3029-34.
170. Oakley EJ, Van Zant G., Age-related changes in niche cells influence hematopoietic stem cell function. Cell Stem Cell. 2010; 6: 93-4.
171. Wu JY, Scadden DT, Kronenberg HM., Role of the osteoblast lineage in the bone marrow hematopoietic niches. J Bone Miner Res. 2009; 24: 759-64.
172. Smith JN, Calvi LM., Concise review: current concepts in bone marrow microenvironmental regulation of hematopoietic stem and progenitor cells. Stem Cells. 2013; 31: 1044-50.
173. Cheng YH, Chitteti BR, Streicher DA, et al. Impact of maturational status on the ability of osteoblasts to enhance the hematopoietic function of stem and progenitor cells. J Bone Miner Res. 2011; 26: 1111-21.
174. Askmyr M, Sims NA, Martin TJ, Purton LE., What is the true nature of the osteoblastic hematopoietic stem cell niche ? Trends Endocrinol Metab. 2009; 20: 303-9.
175. Bianco P., Bone and the hematopoietic niche: a tale of two stem cells. Blood. 2011; 117: 5281-8.
176. Arai F, Hosokawa K, Toyama H, Matsumoto Y, Suda T., Role of N-cadherin in the regulation of hematopoietic stem cells in the bone marrow niche. Ann NY Acad Sci. 2012; 1266: 72-7.
177. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425: 836-41.
178. Haug JS, He XC, Grindley JC, et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell. 2008; 2: 367-79.
179. Gonzalez-Nieto D, Li L, Kohler A, et al. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012; 119: 5144-54.
180. Morrison SJ, Spradling AC., Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008; 132: 598-611.
181. Lawless C, Wang C, Jurk D, Merz A, Zglinicki T, Passos JF., Quantitative assessment of markers for cell senescence. Exp Gerontol. 2010; 45: 772-8.
182. Howcroft TK, Campisi J, Louis GB, et al. The role of inflammation in age-related disease. Aging (Albany NY). 2013; 5: 84-93.