Pro-inflammatory Cytokines: Cellular and Molecular Drug Targets for Glucocorticoid-induced-osteoporosis via Osteocyte

Author(s): Tiantian Wang, Xijie Yu*, Chengqi He*.

Journal Name: Current Drug Targets

Volume 20 , Issue 1 , 2019

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Graphical Abstract:


Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-α and IL-6. On the other hand, TNF-α and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-α can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-α and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-α and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP.

Keywords: TNF-α, IL-6, osteocytes, osteoclasts, osteoblasts, GIOP.

Crawford BA, Liu PY, Kean MT, et al. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab 2003; 88(7): 3167-76.
Ronchetti S, Migliorati G, Riccardi C. GILZ as a mediator of the anti-inflammatory effects of glucocorticoids. Front Endocrinol (Lausanne) 2015; 6: 170.
Pan G, Cao J, Yang N, et al. Role of glucocorticoid-induced leucine zipper (GILZ) in bone acquisition. J Biol Chem 2014; 289(28): 19373-82.
Yang N, Baban B, Isales CM, et al. Role of glucocorticoid-induced leucine zipper (GILZ) in inflammatory bone loss. PLoS One 2017; 12(8): e0181133.
Schorlemmer S, Ignatius A, Claes L, et al. Inhibition of cortical and cancellous bone formation in glucocorticoid-treated OVX sheep. Bone 2005; 37(4): 491-6.
Ciccarelli F, De Martinis M, Ginaldi L. Glucocorticoids in patients with rheumatic diseases: friends or enemies of bone? Curr Med Chem 2015; 22(5): 596-603.
Guler-Yuksel M, Hoes JN, Bultink IEM, et al. Glucocorticoids, Inflammation and Bone. Calcif Tissue Int 2018.
Hayashi K, Yamaguchi T, Yano S, et al. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 2009; 379(2): 261-6.
Jia D, O’Brien CA, Stewart SA, et al. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006; 147(12): 5592-9.
Dempster DW, Moonga BS, Stein LS, et al. Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis. J Endocrinol 1997; 154(3): 397-406.
Bonewald LF. Osteocytes as dynamic multifunctional cells. Ann N Y Acad Sci 2007; 1116: 281-90.
Noble BS. The osteocyte lineage. Arch Biochem Biophys 2008; 473(2): 106-11.
Cardoso L, Herman BC, Verborgt O, et al. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J Bone Miner Res 2009; 24(4): 597-605.
Tatsumi S, Ishii K, Amizuka N, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 2007; 5(6): 464-75.
Weinstein RS. Is long-term glucocorticoid therapy associated with a high prevalence of asymptomatic vertebral fractures? Nat Clin Pract Endocrinol Metab 2007; 3(2): 86-7.
Weinstein RS, Chen JR, Powers CC, et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 2002; 109(8): 1041-8.
Lane NE, Yao W, Balooch M, 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. J Bone Miner Res 2006; 21(3): 466-76.
Chen H, Senda T, Kubo KY. The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. Med Mol Morphol 2015; 48(2): 61-8.
Sun P, Cai DH, Li QN, et al. Effects of alendronate and strontium ranelate on cancellous and cortical bone mass in glucocorticoid-treated adult rats. Calcif Tissue Int 2010; 86(6): 495-501.
Satpathy S, Patra A, Ahirwar B. Experimental techniques for screening of antiosteoporotic activity in postmenopausal osteoporosis. J Complement Integr Med 2015; 12(4): 251-66.
Takahata M, Maher JR, Juneja SC, et al. Mechanisms of bone fragility in a mouse model of glucocorticoid-treated rheumatoid arthritis: implications for insufficiency fracture risk. Arthritis Rheum 2012; 64(11): 3649-59.
Li X, Zhou ZY, Zhang YY, et al. IL-6 contributes to the defective osteogenesis of bone marrow stromal cells from the vertebral body of the glucocorticoid-induced osteoporotic mouse. PLoS One 2016; 11(4): e0154677.
Bakker AD, Kulkarni RN, Klein-Nulend J, et al. IL-6 alters osteocyte signaling toward osteoblasts but not osteoclasts. J Dent Res 2014; 93(4): 394-9.
Vincent C, Findlay DM, Welldon KJ, et al. Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFalpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. J Bone Miner Res 2009; 24(8): 1434-49.
Bakker AD, Silva VC, Krishnan R, et al. Tumor necrosis factor alpha and interleukin-1beta modulate calcium and nitric oxide signaling in mechanically stimulated osteocytes. Arthritis Rheum 2009; 60(11): 3336-45.
Schaffler MB, Kennedy OD. Osteocyte signaling in bone. Curr Osteoporos Rep 2012; 10(2): 118-25.
Aguirre JI, Plotkin LI, Stewart SA, et al. Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Miner Res 2006; 21(4): 605-15.
Kogianni G, Noble BS. The biology of osteocytes. Curr Osteoporos Rep 2007; 5(2): 81-6.
Yoshiko Y, Wang H, Minamizaki T, et al. Mineralized tissue cells are a principal source of FGF23. Bone 2007; 40(6): 1565-73.
Wang H, Yoshiko Y, Yamamoto R, et al. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Miner Res 2008; 23(6): 939-48.
Doty SB. Morphological evidence of gap junctions between bone cells. Calcif Tissue Int 1981; 33(5): 509-12.
Marotti G, Ferretti M, Muglia MA, et al. A quantitative evaluation of osteoblast-osteocyte relationships on growing endosteal surface of rabbit tibiae. Bone 1992; 13(5): 363-8.
Stains JP, Civitelli R. Cell-to-cell interactions in bone. Biochem Biophys Res Commun 2005; 328(3): 721-7.
Yellowley CE, Li Z, Zhou Z, et al. Functional gap junctions between osteocytic and osteoblastic cells. J Bone Miner Res 2000; 15(2): 209-17.
Xu H, Gu S, Riquelme MA, et al. Connexin 43 channels are essential for normal bone structure and osteocyte viability. J Bone Miner Res 2015; 30(3): 436-48.
Lecanda F, Warlow PM, Sheikh S, et al. Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol 2000; 151(4): 931-44.
Jiang JX, Cheng B. Mechanical stimulation of gap junctions in bone osteocytes is mediated by prostaglandin E2. Cell Commun Adhes 2001; 8(4-6): 283-8.
Cheng B, Kato Y, Zhao S, et al. PGE(2) is essential for gap junction-mediated intercellular communication between osteocyte-like MLO-Y4 cells in response to mechanical strain. Endocrinology 2001; 142(8): 3464-73.
Cherian PP, Siller-Jackson AJ, Gu S, et al. Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell 2005; 16(7): 3100-6.
Jiang JX, Cherian PP. Hemichannels formed by connexin 43 play an important role in the release of prostaglandin E(2) by osteocytes in response to mechanical strain. Cell Commun Adhes 2003; 10(4-6): 259-64.
Cherian PP, Cheng B, Gu S, et al. Effects of mechanical strain on the function of Gap junctions in osteocytes are mediated through the prostaglandin EP2 receptor. J Biol Chem 2003; 278(44): 43146-56.
Xia X, Batra N, Shi Q, et al. Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/beta-catenin signaling. Mol Cell Biol 2010; 30(1): 206-19.
Zaman G, Pitsillides AA, Rawlinson SC, et al. Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J Bone Miner Res 1999; 14(7): 1123-31.
Mancini L, Moradi-Bidhendi N, Becherini L, et al. The biphasic effects of nitric oxide in primary rat osteoblasts are cGMP dependent. Biochem Biophys Res Commun 2000; 274(2): 477-81.
Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 2002; 110(6): 771-81.
Sheng MH, Zhou XD, Bonewald LF, et al. Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. Bone 2013; 52(1): 133-44.
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(7): 1095-101.
Fujita T, Azuma Y, Fukuyama R, et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. The J Cell Biol 2004; 166(1): 85-95.
Reijnders CM, Bravenboer N, Tromp AM, et al. Effect of mechanical loading on insulin-like growth factor-I gene expression in rat tibia. J Endocrinol 2007; 192(1): 131-40.
Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 2014; 6(2): 48-57.
Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003; 22(23): 6267-76.
Balemans W, Ebeling M, Patel N, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 2001; 10(5): 537-43.
Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 2001; 68(3): 577-89.
Li X, Ominsky MS, Niu QT, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008; 23(6): 860-9.
Lin C, Jiang X, Dai Z, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 2009; 24(10): 1651-61.
Loots GG, Kneissel M, Keller H, et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 2005; 15(7): 928-35.
Rhee Y, Allen MR, Condon K, et al. PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. J Bone Miner Res 2011; 26(5): 1035-46.
Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005; 280(20): 19883-7.
Li X, Liu P, Liu W, et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 2005; 37(9): 945-52.
Li J, Sarosi I, Cattley RC, et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 2006; 39(4): 754-66.
Li X, Grisanti M, Fan W, et al. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J Bone Miner Res 2011; 26(11): 2610-21.
Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011; 377(9773): 1276-87.
Balemans W, Piters E, Cleiren E, et al. The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int 2008; 82(6): 445-53.
Watkins M, Grimston SK, Norris JY, et al. Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Mol Biol Cell 2011; 22(8): 1240-51.
Zhang Y, Paul EM, Sathyendra V, et al. Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone. PLoS One 2011; 6(8): e23516.
Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res 2000; 15(1): 60-7.
Emerton KB, Hu B, Woo AA, et al. Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone 2010; 46(3): 577-83.
Cabahug-Zuckerman P, Frikha-Benayed D, Majeska RJ, et al. Osteocyte apoptosis caused by hindlimb unloading is required to trigger osteocyte RANKL production and subsequent resorption of cortical and trabecular bone in mice femurs. J Bone Miner Res 2016; 31(7): 1356-65.
Bentolila V, Boyce TM, Fyhrie DP, et al. Intracortical remodeling in adult rat long bones after fatigue loading. Bone 1998; 23(3): 275-81.
Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 2005; 19(13): 1842-4.
Yang J, Shah R, Robling AG, et al. HMGB1 is a bone-active cytokine. J Cell Physiol 2008; 214(3): 730-9.
Bidwell JP, Yang J, Robling AG. Is HMGB1 an osteocyte alarmin? J Cell Biochem 2008; 103(6): 1671-80.
Jilka RL, Noble B, Weinstein RS. Osteocyte apoptosis. Bone 2013; 54(2): 264-71.
Kennedy OD, Herman BC, Laudier DM, et al. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 2012; 50(5): 1115-22.
Kramer I, Halleux C, Keller H, et al. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol 2010; 30(12): 3071-85.
Harris SE, MacDougall M, Horn D, et al. Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects. Bone 2012; 50(1): 42-53.
Heino TJ, Hentunen TA, Vaananen HK. Osteocytes inhibit osteoclastic bone resorption through transforming growth factor-beta: enhancement by estrogen. J Cell Biochem 2002; 85(1): 185-97.
Crane JL, Cao X. Bone marrow mesenchymal stem cells and TGF-beta signaling in bone remodeling. J Clin Invest 2014; 124(2): 466-72.
Tan SD, Kuijpers-Jagtman AM, Semeins CM, et al. Fluid shear stress inhibits TNFalpha-induced osteocyte apoptosis. J Dent Res 2006; 85(10): 905-9.
Collin-Osdoby P, Rothe L, Bekker S, et al. Decreased nitric oxide levels stimulate osteoclastogenesis and bone resorption both in vitro and in vivo on the chick chorioallantoic membrane in association with neoangiogenesis. J Bone Miner Res 2000; 15(3): 474-88.
Lutter AH, Hempel U, Anderer U, et al. Biphasic influence of PGE2 on the resorption activity of osteoclast-like cells derived from human peripheral blood monocytes and mouse RAW264.7 cells. Prostaglandins Leukot Essent Fatty Acids 2016; 111: 1-7.
Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113(4): 561-8.
Larsson T, Yu X, Davis SI, et al. A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab 2005; 90(4): 2424-7.
Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med 2000; 11(3): 279-303.
Quarles LD, Drezner MK. Pathophysiology of X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemia: a perPHEXing problem. J Clin Endocrinol Metab 2001; 86(2): 494-6.
Sitara D, Razzaque MS, Hesse M, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004; 23(7): 421-32.
Saito H, Maeda A, Ohtomo S, et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005; 280(4): 2543-9.
Sato T, Tominaga Y, Ueki T, et al. Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism. Am J Kidney Dis 2004; 44(3): 481-7.
Meir T, Durlacher K, Pan Z, et al. Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription. Kidney Int 2014; 86(6): 1106-15.
Lavi-Moshayoff V, Wasserman G, Meir T, et al. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 2010; 299(4): F882-9.
Rhee Y, Bivi N, Farrow E, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 2011; 49(4): 636-43.
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007; 117(12): 4003-8.
Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281(10): 6120-3.
Krajisnik T, Bjorklund P, Marsell R, et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007; 195(1): 125-31.
Brennan-Speranza TC, Henneicke H, Gasparini SJ, et al. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest 2012; 122(11): 4172-89.
Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007; 130(3): 456-69.
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.
Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 2002; 966: 73-81.
O’Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004; 145(4): 1835-41.
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.
Jia J, Yao W, Guan M, et al. Glucocorticoid dose determines osteocyte cell fate. FASEB J 2011; 25(10): 3366-76.
Kitase Y, Barragan L, Qing H, et al. Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the beta-catenin and PKA pathways. J Bone Miner Res 2010; 25(12): 2657-68.
Shen H, Grimston S, Civitelli R, et al. Deletion of connexin43 in osteoblasts/osteocytes leads to impaired muscle formation in mice. J Bone Miner Res 2015; 30(4): 596-605.
Gao J, Cheng TS, Qin A, et al. Glucocorticoid impairs cell-cell communication by autophagy-mediated degradation of connexin 43 in osteocytes. Oncotarget 2016; 7(19): 26966-78.
Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem 2007; 282(16): 11613-7.
Pufe T, Scholz-Ahrens KE, Franke AT, et al. The role of vascular endothelial growth factor in glucocorticoid-induced bone loss: evaluation in a minipig model. Bone 2003; 33(6): 869-76.
Athanasopoulos AN, Schneider D, Keiper T, et al. Vascular endothelial growth factor (VEGF)-induced up-regulation of CCN1 in osteoblasts mediates proangiogenic activities in endothelial cells and promotes fracture healing. J Biol Chem 2007; 282(37): 26746-53.
Weinstein RS. Glucocorticoids, osteocytes, and skeletal fragility: the role of bone vascularity. Bone 2010; 46(3): 564-70.
Wang Y, Wan C, Deng L, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 2007; 117(6): 1616-26.
Rae M, Mohamad A, Price D, et al. Cortisol inactivation by 11beta-hydroxysteroid dehydrogenase-2 may enhance endometrial angiogenesis via reduced thrombospondin-1 in heavy menstruation. J Clin Endocrinol Metab 2009; 94(4): 1443-50.
Goans RE, Weiss GH, Abrams SA, et al. Calcium tracer kinetics show decreased irreversible flow to bone in glucocorticoid treated patients. Calcif Tissue Int 1995; 56(6): 533-5.
Drescher W, Li H, Qvesel D, et al. Vertebral blood flow and bone mineral density during long-term corticosteroid treatment: An experimental study in immature pigs. Spine 2000; 25(23): 3021-5.
Reeve J, Arlot M, Wootton R, et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. J Clin Endocrinol Metab 1988; 66(6): 1124-31.
Boulos P, Ioannidis G, Adachi JD. Glucocorticoid-induced osteoporosis. Curr Rheumatol Rep 2000; 2(1): 53-61.
Dupond JL, Mahammedi H, Prie D, et al. Oncogenic osteomalacia: diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case. Bone 2005; 36(3): 375-8.
Liu S, Tang W, Zhou J, et al. Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in Hyp mice. Am J Physiol Endocrinol Metab 2007; 293(6): E1636-44.
Li H, Qian W, Weng X, et al. Glucocorticoid receptor and sequential P53 activation by dexamethasone mediates apoptosis and cell cycle arrest of osteoblastic MC3T3-E1 cells. PLoS One 2012; 7(6): e37030.
Liu Y, Porta A, Peng X, et al. Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by calbindin-D28k. J Bone Miner Res 2004; 19(3): 479-90.
Yao W, Cheng Z, Busse C, et al. Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum 2008; 58(6): 1674-86.
Smith E, Coetzee GA, Frenkel B. Glucocorticoids inhibit cell cycle progression in differentiating osteoblasts via glycogen synthase kinase-3beta. J Biol Chem 2002; 277(20): 18191-7.
Stahn C, Lowenberg M, Hommes DW, et al. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol 2007; 275(1-2): 71-8.
Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999; 140(10): 4382-9.
Sivagurunathan S, Muir MM, Brennan TC, et al. Influence of glucocorticoids on human osteoclast generation and activity. J Bone Miner Res 2005; 20(3): 390-8.
Plotkin LI, Mathov I, Aguirre JI, et al. Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs. Am J Physiol Cell Physiol 2005; 289(3): C633-43.
Bellido T. Antagonistic interplay between mechanical forces and glucocorticoids in bone: a tale of kinases. J Cell Biochem 2010; 111(1): 1-6.
Plotkin LI, Manolagas SC, Bellido T. Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis. J Biol Chem 2007; 282(33): 24120-30.
Almeida M, Han L, Ambrogini E, et al. Glucocorticoids and tumor necrosis factor alpha increase oxidative stress and suppress Wnt protein signaling in osteoblasts. J Biol Chem 2011; 286(52): 44326-35.
Besedovsky H, del Rey A, Sorkin E, et al. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986; 233(4764): 652-4.
Escher G, Galli I, Vishwanath BS, et al. Tumor necrosis factor alpha and interleukin 1beta enhance the cortisone/cortisol shuttle. J Exp Med 1997; 186(2): 189-98.
Heiniger CD, Rochat MK, Frey FJ, et al. TNF-alpha enhances intracellular glucocorticoid availability. FEBS Lett 2001; 507(3): 351-6.
Wang TT, He CQ, Yu XJ. Pro-inflammatory cytokines: new potential therapeutic targets for obesity-related bone disorders. Curr Drug Targets 2017; 18(14): 1664-75.
Cheung WY, Simmons CA, You L. Osteocyte apoptosis regulates osteoclast precursor adhesion via osteocytic IL-6 secretion and endothelial ICAM-1 expression. Bone 2012; 50(1): 104-10.
Cheung WY, Liu C, Tonelli-Zasarsky RM, et al. Osteocyte apoptosis is mechanically regulated and induces angiogenesis in vitro. J Orthop Res 2011; 29(4): 523-30.
Kohno S, Kaku M, Tsutsui K, et al. Expression of vascular endothelial growth factor and the effects on bone remodeling during experimental tooth movement. J Dent Res 2003; 82(3): 177-82.
Ito N, Wijenayaka AR, Prideaux M, et al. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol 2015; 399: 208-18.
Byun CH, Koh JM, Kim DK, et al. Alpha-lipoic acid inhibits TNF-alpha-induced apoptosis in human bone marrow stromal cells. J Bone Miner Res 2005; 20(7): 1125-35.
Kim BJ, Bae SJ, Lee SY, et al. TNF-alpha mediates the stimulation of sclerostin expression in an estrogen-deficient condition. Biochem Biophys Res Commun 2012; 424(1): 170-5.
Baek K, Hwang HR, Park HJ, et al. TNF-alpha upregulates sclerostin expression in obese mice fed a high-fat diet. J Cell Physiol 2014; 229(5): 640-50.
Yeremenko N, Zwerina K, Rigter G, et al. Tumor necrosis factor and interleukin-6 differentially regulate Dkk-1 in the inflamed arthritic joint. Arthritis Rheumatol 2015; 67(8): 2071-5.
Kogianni G, Mann V, Noble BS. Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Miner Res 2008; 23(6): 915-27.
Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17(10): 1231-4.
Cooper MS. 11beta-Hydroxysteroid dehydrogenase: a regulator of glucocorticoid response in osteoporosis. J Endocrinol Invest 2008; 31(7)(Suppl.): 16-21.
Angeli A, Dovio A, Sartori ML, et al. Interactions between glucocorticoids and cytokines in the bone microenvironment. Ann N Y Acad Sci 2002; 966: 97-107.
Juffer P, Jaspers RT, Lips P, et al. Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes. Am J Physiol Endocrinol Metab 2012; 302(4): E389-95.
Chen W, Ma Y, Ye H, et al. ERK1/2 is involved in cyclic compressive force-induced IL-6 secretion in MLO-Y4 cells. Biochem Biophys Res Commun 2010; 401(3): 339-43.
Zahler S, Kupatt C, Becker BF. Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha. FASEB J 2000; 14(3): 555-64.
Cauley JA, Danielson ME, Boudreau RM, et al. Inflammatory markers and incident fracture risk in older men and women: the health aging and body composition study. J Bone Miner Res 2007; 22(7): 1088-95.
Zheng SX, Vrindts Y, Lopez M, et al. Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis. Maturitas 1997; 26(1): 63-71.
Zhang K, Wang C, Chen Y, et al. Preservation of high-fat diet-induced femoral trabecular bone loss through genetic target of TNF-alpha. Endocrine 2015; 50(1): 239-49.
Wang C, Tian L, Zhang K, et al. Interleukin-6 gene knockout antagonizes high-fat-induced trabecular bone loss. J Mol Endocrinol 2016; 57(3): 161-70.
Toussirot E, Mourot L, Dehecq B, et al. TNFalpha blockade for inflammatory rheumatic diseases is associated with a significant gain in android fat mass and has varying effects on adipokines: a 2-year prospective study. Eur J Nutr 2014; 53(3): 951-61.
Marotte H, Pallot-Prades B, Grange L, et al. A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab. Arthritis Res Ther 2007; 9(3): R61.
Saidenberg-Kermanac’h N, Corrado A, Lemeiter D, et al. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone 2004; 35(5): 1200-7.
Garnero P, Thompson E, Woodworth T, et al. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum 2010; 62(1): 33-43.
Strang AC, Bisoendial RJ, Kootte RS, et al. Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis. Atherosclerosis 2013; 229(1): 174-81.
Antoniou C, Dessinioti C, Katsambas A, et al. Elevated triglyceride and cholesterol levels after intravenous antitumour necrosis factor-alpha therapy in a patient with psoriatic arthritis and psoriasis vulgaris. Br J Dermatol 2007; 156(5): 1090-1.
Lang VR, Englbrecht M, Rech J, et al. Risk of infections in rheumatoid arthritis patients treated with tocilizumab. Rheumatology (Oxford) 2012; 51(5): 852-7.
Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295(19): 2275-85.

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Year: 2019
Page: [1 - 15]
Pages: 15
DOI: 10.2174/1389450119666180405094046
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