Autophagy: A Promising Target for Age-related Osteoporosis

Author(s): Tiantian Wang, Hongchen He, Shaxin Liu, Chengsen Jia, Ziyan Fan, Can Zhong, Jiadan Yu, Honghong Liu, Chengqi He*.

Journal Name: Current Drug Targets

Volume 20 , Issue 3 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Autophagy is a process the primary role of which is to clear up damaged cellular components such as long-lived proteins and organelles, thus participating in the conservation of different cells. Osteoporosis associated with aging is characterized by consistent changes in bone metabolism with suppression of bone formation as well as increased bone resorption. In advanced age, not only bone mass but also bone strength decrease in both sexes, resulting in an increased incidence of fractures. Clinical and animal experiments reveal that age-related bone loss is associated with many factors such as accumulation of autophagy, increased levels of reactive oxygen species, sex hormone deficiency, and high levels of endogenous glucocorticoids. Available basic and clinical studies indicate that age-associated factors can regulate autophagy. Those factors play important roles in bone remodeling and contribute to decreased bone mass and bone strength with aging. In this review, we summarize the mechanisms involved in bone metabolism related to aging and autophagy, supplying a theory for therapeutic targets to rescue bone mass and bone strength in older people.

Keywords: Age-related osteoporosis, autophagy, BMSCs, osteoblasts, osteoclasts, osteocytes.

Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013; 153(6): 1194-217.
Anton B, Vitetta L, Cortizo F, et al. Can we delay aging? The biology and science of aging. Ann N Y Acad Sci 2005; 1057: 525-35.
D’Amelio P, Isaia GC. Male osteoporosis in the elderly. Int J Endocrinol 2015; 2015: 907689.
Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3(4): 393-403.
Capulli M, Paone R, Rucci N. Osteoblast and osteocyte: Games without frontiers. Arch Biochem Biophys 2014; 561: 3-12.
Charles JF, Aliprantis AO. Osteoclasts: More than ‘bone eaters’. Trends Mol Med 2014; 20(8): 449-59.
Schaffler MB, Cheung WY, Majeska R, et al. Osteocytes: Master orchestrators of bone. Calcif Tissue Int 2014; 94(1): 5-24.
Wang T, Yu X, He C. Pro-inflammatory cytokines: Cellular and molecular drug targets for glucocorticoid-induced-osteoporosis via osteocyte. Curr Drug Targets 2019; 20(1): 1-15.
Shen G, Ren H, Shang Q, et al. Autophagy as a target for glucocorticoid- induced osteoporosis therapy. Cell Mol Life Sci 2018; 75(15): 2683-93
Vessoni AT, Muotri AR, Okamoto OK. Autophagy in stem cell maintenance and differentiation. Stem Cells Dev 2012; 21(4): 513-20.
Marino G, Niso-Santano M, Baehrecke EH, et al. Self-consumption: The interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014; 15(2): 81-94.
Nollet M, Santucci-Darmanin S, Breuil V, et al. Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy 2014; 10(11): 1965-77.
Shen G, Ren H, Shang Q, et al. Autophagy as a target for glucocorticoid-induced osteoporosis therapy. Cell Mol Life Sci 2018. [Epub ahead of print].
Chen K, Yang YH, Jiang SD, et al. Decreased activity of osteocyte autophagy with aging may contribute to the bone loss in senile population. Histochem Cell Biol 2014; 142(3): 285-95.
Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell 2011; 146(5): 682-95.
Crockett JC, Rogers MJ, Coxon FP, et al. Bone remodelling at a glance. J Cell Sci 2011; 124(Pt 7): 991-8.
Goudarzi M, Mir N, Mousavi-Kamazani M, et al. Biosynthesis and characterization of silver nanoparticles prepared from two novel natural precursors by facile thermal decomposition methods. Sci Rep 2016; 6: 32539.
Goudarzi M, Mousavi-Kamazani M, Salavati-Niasari M. Zinc oxide nanoparticles: Solvent-free synthesis, characterization and application as heterogeneous nanocatalyst for photodegradation of dye from aqueous phase. J Mater Sci Mater Electron 2017; 28(12): 8423-8.
Mousavi-Kamazani M, Salavati-Niasari M, Goudarzi M, Zarghami Z. Hydrothermal synthesis of CdIn2S4 nanostructures using new starting reagent for elevating solar cells efficiency. J Mol Liq 2017; 242: 653-61.
Goudarzi M, Ghanbari D, Salavati-Niasari M, Ahmadi A. Synthesis and characterization of Al(OH)3, Al2O3 nanoparticles and polymeric nanocomposites. J Cluster Sci 2016; 242(1): 25-38.
Salavati-Niasari M, Goudarzi M. Controllable synthesis of new Tl2S2O3 nanostructures via hydrothermal process; characterization and investigation photocatalytic activity for degradation of some anionic dyes. J Mol Liq 2016; 219: 851-7.
Goudarzi M, Bazarganipour M, Salavati-Niasari M. Synthesis, characterization and degradation of organic dye over Co3O4. nanoparticles prepared from new binuclear complex precursors. RSC Advances 2014; 4(87): 46517-20.
Salavati-Niasari MGZZM. Novel and solvent-free cochineal-assisted synthesis of Ag–Al2O3 nanocomposites via solid-state thermal decomposition route: characterization and photocatalytic activity assessment. J Mater Sci Mater Electron 2016; 27(9): 9789-97.
Motaghedifard MGMS-NM. Semiconductive Tl2O3 nanoparticles: Facile synthesis in liquid phase, characterization and its applications as photocatalytic substrate and electrochemical sensor. J Mol Liq 2016; 219: 720-7.
Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 1988; 81(6): 1804-9.
Riggs BL, Melton Iii LJ 3rd, Robb RA, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res 2004; 19(12): 1945-54.
Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin North Am 2005; 34(4): 1015-30. [xi.].
Zebaze RM, Ghasem-Zadeh A, Bohte A, et al. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 2010; 375(9727): 1729-36.
Turner CH. Bone strength: current concepts. Ann N Y Acad Sci 2006; 1068: 429-46.
Han ZH, Palnitkar S, Rao DS, et al. Effect of ethnicity and age or menopause on the structure and geometry of iliac bone. J Bone Miner Res 1996; 11(12): 1967-75.
Schaffler MB, Burr DB. Stiffness of compact bone: effects of porosity and density. J Biomech 1988; 21(1): 13-6.
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(37): 27285-97.
Jilka RL, O’Brien CA. The role of osteocytes in age-related bone loss. Curr Osteoporos Rep 2016; 14(1): 16-25.
Vanhooren V, Libert C. The mouse as a model organism in aging research: usefulness, pitfalls and possibilities. Ageing Res Rev 2013; 12(1): 8-21.
Ferguson VL, Ayers RA, Bateman TA, et al. Bone development and age-related bone loss in male C57BL/6J mice. Bone 2003; 33(3): 387-98.
Bell KL, Loveridge N, Power J, et al. Structure of the femoral neck in hip fracture: cortical bone loss in the inferoanterior to superoposterior axis. J Bone Miner Res 1999; 14(1): 111-9.
Nelson JF, Felicio LS, Osterburg HH, et al. Differential contributions of ovarian and extraovarian factors to age-related reductions in plasma estradiol and progesterone during the estrous cycle of C57BL/6J mice. Endocrinology 1992; 130(2): 805-10.
Mobbs CV, Cheyney D, Sinha YN, et al. Age-correlated and ovary-dependent changes in relationships between plasma estradiol and luteinizing hormone, prolactin, and growth hormone in female C57BL/6J mice. Endocrinology 1985; 116(2): 813-20.
Finch CE, Jonec V, Wisner JR Jr, et al. Hormone production by the pituitary and testes of male C57BL/6J mice during aging. Endocrinology 1977; 101(4): 1310-7.
Recker R, Lappe J, Davies KM, et al. Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res 2004; 19(10): 1628-33.
Young AR, Narita M. Connecting autophagy to senescence in pathophysiology. Curr Opin Cell Biol 2010; 22(2): 234-40.
Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011; 469(7330): 323-35.
Fu Q, Shi H, Ren Y, et al. Bovine viral diarrhea virus infection induces autophagy in MDBK cells. J Microbiol 2014; 52(7): 619-25.
Dupont N, Lacas-Gervais S, Bertout J, et al. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe 2009; 6(2): 137-49.
Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8(11): 931-7.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132(1): 27-42.
Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol 2012; 821: 1-14.
Inoki K, Kim J, Guan KL. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 2012; 52: 381-400.
Tooze SA, Yoshimori T. The origin of the autophagosomal membrane. Nat Cell Biol 2010; 12(9): 831-5.
Mari M, Tooze SA, Reggiori F. The puzzling origin of the autophagosomal membrane. F1000 Biol Rep 2011; 3: 25.
Chen D, Fan W, Lu Y, et al. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Mol Cell 2012; 45(5): 629-41.
Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep 2008; 9(9): 859-64.
Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005; 169(3): 425-34.
Kim KH, Lee MS. Autophagy as a crosstalk mediator of metabolic organs in regulation of energy metabolism. Rev Endocr Metab Disord 2014; 15(1): 11-20.
Itakura E, Kishi C, Inoue K, et al. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008; 19(12): 5360-72.
Axe EL, Walker SA, Manifava M, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 2008; 182(4): 685-701.
Canalis E, Mazziotti G, Giustina A, et al. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007; 18(10): 1319-28.
Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell 2010; 140(3): 313-26.
Kuballa P, Nolte WM, Castoreno AB, et al. Autophagy and the immune system. Annu Rev Immunol 2012; 30: 611-46.
Kenyon CJ. The genetics of ageing. Nature 2010; 464(7288): 504-12.
Wu JJ, Quijano C, Chen E, et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Albany NY) 2009; 1(4): 425-37.
Lipinski MM, Zheng B, Lu T, et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc Natl Acad Sci USA 2010; 107(32): 14164-9.
Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 2010; 62(3): 791-801.
Yen WL, Klionsky DJ. How to live long and prosper: autophagy, mitochondria, and aging. Physiology (Bethesda) 2008; 23: 248-62.
Challen C, Brown H, Cai C, et al. Mitochondrial DNA mutations in head and neck cancer are infrequent and lack prognostic utility. Br J Cancer 2011; 104(8): 1319-24.
Almeida M. Aging mechanisms in bone. Bonekey Rep 2012; •••: 1.
Dickinson DA, Forman HJ. Glutathione in defense and signaling: lessons from a small thiol. Ann N Y Acad Sci 2002; 973: 488-504.
Lean JM, Davies JT, Fuller K, et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 2003; 112(6): 915-23.
Jagger CJ, Lean JM, Davies JT, et al. Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. Endocrinology 2005; 146(1): 113-8.
Tyner SD, Venkatachalam S, Choi J, et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 2002; 415(6867): 45-53.
de Boer J, Andressoo JO, de Wit J, et al. Premature aging in mice deficient in DNA repair and transcription. Science 2002; 296(5571): 1276-9.
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(11): 2682-94.
Huang J, Lam GY, Brumell JH. Autophagy signaling through reactive oxygen species. Antioxid Redox Signal 2011; 14(11): 2215-31.
Chen Y, Azad MB, Gibson SB. Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 2009; 16(7): 1040-52.
Scherz-Shouval R, Shvets E, Fass E, et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2007; 26(7): 1749-60.
Droge W, Schipper HM. Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 2007; 6(3): 361-70.
Wei Y, Pattingre S, Sinha S, et al. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 2008; 30(6): 678-88.
Park KJ, Lee SH, Lee CH, et al. Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochem Biophys Res Commun 2009; 382(4): 726-9.
Zhang XY, Wu XQ, Deng R, et al. Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells. Cell Signal 2013; 25(1): 150-8.
Alexander A, Cai SL, Kim J, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA 2010; 107(9): 4153-8.
Li L, Chen Y, Gibson SB. Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal 2013; 25(1): 50-65.
McClung JM, Judge AR, Powers SK, et al. p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol 2010; 298(3): C542-9.
Luo Y, Zou P, Zou J, et al. Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKalpha dependent manner. Exp Gerontol 2011; 46(11): 860-7.
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(11): 2414-30.
Lee JW, Park S, Takahashi Y, et al. The association of AMPK with ULK1 regulates autophagy. PLoS One 2010; 5(11): e15394.
Sanchez AM, Csibi A, Raibon A, et al. AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1. J Cell Biochem 2012; 113(2): 695-710.
Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002; 23(3): 279-302.
Vanderschueren D, Vandenput L, Boonen S, et al. Androgens and bone. Endocr Rev 2004; 25(3): 389-425.
Seeman E. Clinical review 137: Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 2001; 86(10): 4576-84.
Diab DL, Watts NB. Postmenopausal osteoporosis. Curr Opin Endocrinol Diabetes Obes 2013; 20(6): 501-9.
Lindsay R, Hart DM, Aitken JM, et al. Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet 1976; 1(7968): 1038-41.
Khosla S, Atkinson EJ, Melton LJ 3rd, et al. Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population-based study. J Clin Endocrinol Metab 1997; 82(5): 1522-7.
Hughes DE, Dai A, Tiffee JC, et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 1996; 2(10): 1132-6.
Falahati-Nini A, Riggs BL, Atkinson EJ, et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000; 106(12): 1553-60.
Leder BZ, LeBlanc KM, Schoenfeld DA, et al. Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 2003; 88(1): 204-10.
Cauley JA. Estrogen and bone health in men and womenSteroids 2015; 99(Pt A): 11-5
Eghbali-Fatourechi G, Khosla S, Sanyal A, et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003; 111(8): 1221-30.
Hofbauer LC, Khosla S, Dunstan CR, et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999; 140(9): 4367-70.
Yasuda H, Shima N, Nakagawa N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 1998; 139(3): 1329-37.
Hofbauer LC, Lacey DL, Dunstan CR, et al. Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 1999; 25(3): 255-9.
Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 1992; 257(5066): 88-91.
Ammann P, Rizzoli R, Bonjour JP, et al. Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest 1997; 99(7): 1699-703.
Charatcharoenwitthaya N, Khosla S, Atkinson EJ, et al. Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res 2007; 22(5): 724-9.
Srivastava S, Toraldo G, Weitzmann MN, et al. Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem 2001; 276(12): 8836-40.
Shevde NK, Bendixen AC, Dienger KM, et al. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 2000; 97(14): 7829-34.
Majeska RJ, Ryaby JT, Einhorn TA. Direct modulation of osteoblastic activity with estrogen. J Bone Joint Surg Am 1994; 76(5): 713-21.
Qu Q, Perala-Heape M, Kapanen A, et al. Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone 1998; 22(3): 201-9.
Yang Y, Zheng X, Li B, et al. Increased activity of osteocyte autophagy in ovariectomized rats and its correlation with oxidative stress status and bone loss. Biochem Biophys Res Commun 2014; 451(1): 86-92.
Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab 2012; 23(11): 576-81.
Choi S, Shin H, Song H, et al. Suppression of autophagic activation in the mouse uterus by estrogen and progesterone. J Endocrinol 2014; 221(1): 39-50.
Yang YH, Chen K, Li B, et al. Estradiol inhibits osteoblast apoptosis via promotion of autophagy through the ER-ERK-mTOR pathway. Apoptosis 2013; 18(11): 1363-75.
Brincat SD, Borg M, Camilleri G, et al. The role of cytokines in postmenopausal osteoporosis. Minerva Ginecol 2014; 66(4): 391-407.
Cook KL, Shajahan AN, Clarke R. Autophagy and endocrine resistance in breast cancer. (review) Expert Rev Anticancer Ther 2011; 11(8): 1283-94.
Viedma-Rodriguez R, Baiza-Gutman L, Salamanca-Gomez F, et al. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer. Oncol Rep 2014; 32(1): 3-15. [review].
Weinstein RS, Wan C, Liu Q, et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 2010; 9(2): 147-61.
Weinstein RS. Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin North Am 2012; 41(3): 595-611.
Wilkinson CW, Petrie EC, Murray SR, et al. Human glucocorticoid feedback inhibition is reduced in older individuals: evening study. J Clin Endocrinol Metab 2001; 86(2): 545-50.
Laane E, Tamm KP, Buentke E, et al. Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. Cell Death Differ 2009; 16(7): 1018-29.
Jiang L, Xu L, Xie J, et al. Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells. Cancer Biol Ther 2015; 16(3): 466-76.
Jia L, Dourmashkin RR, Allen PD, et al. Inhibition of autophagy abrogates tumour necrosis factor alpha induced apoptosis in human T-lymphoblastic leukaemic cells. Br J Haematol 1997; 98(3): 673-85.
Xia X, Kar R, Gluhak-Heinrich J, et al. Glucocorticoid-induced autophagy in osteocytes. J Bone Miner Res 2010; 25(11): 2479-88.
Piemontese M, Onal M, Xiong J, et al. Suppression of autophagy in osteocytes does not modify the adverse effects of glucocorticoids on cortical bone. Bone 2015; 75: 18-26.
Rizzoli R, Bonjour JP. Dietary protein and bone health. J Bone Miner Res 2004; 19(4): 527-31.
Blomberg Jensen M. Vitamin D metabolism, sex hormones, and male reproductive function. Reproduction 2012; 144(2): 135-52.
Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010; 17(1): 25-54. quiz 5-6.
St-Arnaud R. The direct role of vitamin D on bone homeostasis. Arch Biochem Biophys 2008; 473(2): 225-30.
van Driel M, Pols HA, van Leeuwen JP. Osteoblast differentiation and control by vitamin D and vitamin D metabolites. Curr Pharm Des 2004; 10(21): 2535-55.
Sooy K, Sabbagh Y, Demay MB. Osteoblasts lacking the vitamin D receptor display enhanced osteogenic potential in vitro. J Cell Biochem 2005; 94(1): 81-7.
Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006; 116(8): 2062-72.
Boonen S, Lips P, Bouillon R, et al. Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2007; 92(4): 1415-23.
Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997; 337(10): 670-6.
Laktasic-Zerjavic N. [The role of vitamin D and calcium in the management of osteoporosis] Reumatizam 2014; 61(2): 80-8.
Hoyer-Hansen M, Nordbrandt SP, Jaattela M. Autophagy as a basis for the health-promoting effects of vitamin D. Trends Mol Med 2010; 16(7): 295-302.
Boonen S, Mohan S, Dequeker J, et al. Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis. J Bone Miner Res 1999; 14(12): 2150-8.
Garnero P, Sornay-Rendu E, Delmas PD. Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women. Lancet 2000; 355(9207): 898-9.
Langlois JA, Rosen CJ, Visser M, et al. Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham Heart Study. J Clin Endocrinol Metab 1998; 83(12): 4257-62.
Richardson A, Liu F, Adamo ML, et al. The role of insulin and insulin-like growth factor-I in mammalian ageing. Best Pract Res Clin Endocrinol Metab 2004; 18(3): 393-406.
van der Horst A, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 2007; 8(6): 440-50.
Sun L, Peng Y, Sharrow AC, et al. FSH directly regulates bone mass. Cell 2006; 125(2): 247-60.
Devleta B, Adem B, Senada S. Hypergonadotropic amenorrhea and bone density: new approach to an old problem. J Bone Miner Metab 2004; 22(4): 360-4.
Abe E, Marians RC, Yu W, et al. TSH is a negative regulator of skeletal remodeling. Cell 2003; 115(2): 151-62.
Feng X, Teitelbaum SL. Osteoclasts: New insights. Bone Res 2013; 1(1): 11-26.
Kim MS, Day CJ, Selinger CI, et al. MCP-1-induced human osteoclast-like cells are tartrate-resistant acid phosphatase, NFATc1, and calcitonin receptor-positive but require receptor activator of NFkappaB ligand for bone resorption. J Biol Chem 2006; 281(2): 1274-85.
Zhou L, Azfer A, Niu J, et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res 2006; 98(9): 1177-85.
Wang K, Niu J, Kim H, et al. Osteoclast precursor differentiation by MCPIP via oxidative stress, endoplasmic reticulum stress, and autophagy. J Mol Cell Biol 2011; 3(6): 360-8.
Chung YH, Jang Y, Choi B, et al. Beclin-1 is required for RANKL-induced osteoclast differentiation. J Cell Physiol 2014; 229(12): 1963-71.
Zhao Y, Chen G, Zhang W, et al. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1alpha/BNIP3 signaling pathway. J Cell Physiol 2012; 227(2): 639-48.
Sambandam Y, Townsend MT, Pierce JJ, et al. Microgravity control of autophagy modulates osteoclastogenesis. Bone 2014; 61: 125-31.
Xiu Y, Xu H, Zhao C, et al. Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation. J Clin Invest 2014; 124(1): 297-310.
DeSelm CJ, Miller BC, Zou W, et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell 2011; 21(5): 966-74.
Chung YH, Yoon SY, Choi B, et al. Microtubule-associated protein light chain 3 regulates Cdc42-dependent actin ring formation in osteoclast. Int J Biochem Cell Biol 2012; 44(6): 989-97.
Lee NK, Choi YG, Baik JY, et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 2005; 106(3): 852-9.
Nomura M, Yoshimura Y, Kikuiri T, et al. Platinum nanoparticles suppress osteoclastogenesis through scavenging of reactive oxygen species produced in RAW264.7 cells. J Pharmacol Sci 2011; 117(4): 243-52.
Kim MS, Yang YM, Son A, et al. RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis. J Biol Chem 2010; 285(10): 6913-21.
Shi J, Wang L, Zhang H, et al. Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy. Bone 2015; 79: 222-32.
Thome R, Lopes SC, Costa FT, et al. Chloroquine: modes of action of an undervalued drug. Immunol Lett 2013; 153(1-2): 50-7.
Lin NY, Chen CW, Kagwiria R, et al. Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss. Ann Rheum Dis 2016; 75(6): 1203-10.
Bosch P, Musgrave DS, Lee JY, et al. Osteoprogenitor cells within skeletal muscle. J Orthop Res 2000; 18(6): 933-44.
Jones E, Churchman SM, English A, et al. Mesenchymal stem cells in rheumatoid synovium: Enumeration and functional assessment in relation to synovial inflammation level. Ann Rheum Dis 2010; 69(2): 450-7.
Song C, Song C, Tong F. Autophagy induction is a survival response against oxidative stress in bone marrow-derived mesenchymal stromal cells. Cytotherapy 2014; 16(10): 1361-70.
Hou J, Han ZP, Jing YY, et al. Autophagy prevents irradiation injury and maintains stemness through decreasing ROS generation in mesenchymal stem cells. Cell Death Dis 2013; 4: e844.
Nuschke A, Rodrigues M, Stolz DB, et al. Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. Stem Cell Res Ther 2014; 5(6): 140.
Pantovic A, Krstic A, Janjetovic K, et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone 2013; 52(1): 524-31.
Liu GY, Jiang XX, Zhu X, et al. ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro. Acta Pharmacol Sin 2015; 36(12): 1473-9.
Qi M, Zhang L, Ma Y, et al. Autophagy maintains the function of bone marrow mesenchymal stem cells to prevent estrogen deficiency-induced osteoporosis. Theranostics 2017; 7(18): 4498-516.
Huitema LF, Vaandrager AB. What triggers cell-mediated mineralization? Front Biosci 2007; 12: 2631-45.
Komori T. Glucocorticoid signaling and bone biology. Horm Metab Res 2016; 48(11): 755-63.
Gan B, Peng X, Nagy T, et al. Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways. J Cell Biol 2006; 175(1): 121-33.
Paszty C, Turner CH, Robinson MK. Sclerostin: A gem from the genome leads to bone-building antibodies. J Bone Miner Res 2010; 25(9): 1897-904.
Li X, Warmington KS, Niu QT, et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J Bone Miner Res 2010; 25(12): 2647-56.
McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014; 370(5): 412-20.
Yao W, Dai W, Jiang L, et al. Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int 2016; 27(1): 283-94.
Zhang S, Liu Y, Liang Q. Low-dose dexamethasone affects osteoblast viability by inducing autophagy via intracellular ROS. Mol Med Rep 2018; 17(3): 4307-16.
Tang YH, Yue ZS, Li GS, et al. Effect of betaecdysterone on glucocorticoidinduced apoptosis and autophagy in osteoblasts. Mol Med Rep 2018; 17(1): 158-64.
Luo D, Ren H, Li T, et al. Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy. Osteoporos Int 2016; 27(3): 1093-101.
Onal M, Piemontese M, Xiong J, et al. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem 2013; 288(24): 17432-40.
Zahm AM, Bohensky J, Adams CS, et al. Bone cell autophagy is regulated by environmental factors. Cells Tissues Organs 2011; 194(2-4): 274-8.
Jia J, Yao W, Guan M, et al. Glucocorticoid dose determines osteocyte cell fate. FASEB J 2011; 25(10): 3366-76.
Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer 2017; 17(9): 528-42.
Sciarretta S, Maejima Y, Zablocki D, et al. The role of autophagy in the heart. Annu Rev Physiol 2018; 80: 1-26.
Ghavami S, Shojaei S, Yeganeh B, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014; 112: 24-49.
Shen G, Ren H, Qiu T, et al. Implications of the interaction between miRNAs and autophagy in osteoporosis. Calcif Tissue Int 2016; 99(1): 1-12.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [354 - 365]
Pages: 12
DOI: 10.2174/1389450119666180626120852
Price: $58

Article Metrics

PDF: 47