Mechanisms of palmitate-induced lipotoxicity in osteocytes
| dc.contributor.author | Al Saedi, Ahmed | |
| dc.contributor.author | Bermeo, Sandra | |
| dc.contributor.author | Plotkin, Lilian | |
| dc.contributor.author | Myers, Damian E. | |
| dc.contributor.author | Duque, Gustavo | |
| dc.date.accessioned | 2019-07-22T19:42:50Z | |
| dc.date.available | 2019-07-22T19:42:50Z | |
| dc.date.issued | 2019-06 | |
| dc.description.abstract | Background: Lipotoxicity is defined as cellular toxicity observed in the presence of an abnormal accumulation of fat and adipocyte-derived factors in non-fat tissues. Palmitic acid (PA), an abundant fatty acid in the bone marrow and particularly in osteoporotic bones, affects osteoblastogenesis and osteoblast function, decreasing their survival through induction of apoptosis and dysfunctional autophagy. In this study, we hypothesized that PA also has a lipotoxic effect on osteocytes in vitro. Methods: Initially, we tested the effect of PA on osteocyte-derived factors DKK1, sclerostin and RANKL. Then, we tested whether PA affects survival and causes apoptosis in osteocytes. Subsequently, we investigated the effect of PA on autophagy by detecting the membrane component LC3-II (Western blot) and staining them and lysosomes with Lysotracker Red dye. Results: PA decreases RANKL, DKK1 and sclerostin expression in osteocytes. In addition, we found that PA induces apoptosis and reduces osteocyte survival. PA also caused autophagy failure identified by a significant increase in LC3-II and a reduced number of autophagosomes/lysosomes in the cytoplasm. Conclusion: In addition to the effects of PA on RANKL, DKK1 and sclerostin expression, which could have significant deleterious impact on bone cell coupling and bone turnover, PA also induced apoptosis and reduced autophagy in osteocytes. Considering that apoptosis and cell dysfunction are two common changes occurring in the osteocytes of osteoporotic bone, our findings suggest that PA could play a role in the pathogenesis of the disease. Suppression of these effects could bring new potential targets for therapeutic interventions in the future. | eng |
| dc.identifier.issn | 87563282 | |
| dc.identifier.uri | https://hdl.handle.net/20.500.12442/3607 | |
| dc.language.iso | eng | eng |
| dc.publisher | Elsevier | spa |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
| dc.rights.accessrights | info:eu-repo/semantics/openAccess | spa |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
| dc.source | Revista BONE | eng |
| dc.source.uri | https://doi.org/10.1016/j.bone.2019.06.016 | eng |
| dc.subject | Palmitic acid | eng |
| dc.subject | Osteocytes | eng |
| dc.subject | Lipotoxicity | eng |
| dc.subject | Fatty acids | eng |
| dc.subject | Osteoporosis | eng |
| dc.subject | Apoptosis | eng |
| dc.subject | Autophagy | eng |
| dc.title | Mechanisms of palmitate-induced lipotoxicity in osteocytes | eng |
| dc.type | article | eng |
| dcterms.references | E.A. Zimmermann, E. Schaible, H. Bale, H.D. Barth, S.Y. Tang, P. Reichert, B. Busse, T. Alliston, J.W. Ager 3rd, R.O. Ritchie, Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales, Proc. Natl. Acad. Sci. U. S. A. 108 (35) (2011) 14416–14421. | eng |
| dcterms.references | D.P. Fyhrie, B.A. Christiansen, Bone material properties and skeletal fragility, Calcif. Tissue Int. 97 (3) (2015) 213–228. | eng |
| dcterms.references | S. Muruganandan, R. Govindarajan, C.J. Sinal, Bone marrow adipose tissue and skeletal health, Current Osteoporosis Reports 16 (4) (2018) 434–442. | eng |
| dcterms.references | L. Singh, S. Tyagi, D. Myers, G. Duque, Good, bad, or ugly: the biological roles of bone marrow fat, Current Osteoporosis Reports 16 (2) (2018) 130–137. | eng |
| dcterms.references | K. Gunaratnam, C. Vidal, J.M. Gimble, G. Duque, Mechanisms of palmitate-induced lipotoxicity in human osteoblasts, Endocrinology 155 (1) (2014) 108–116. | eng |
| dcterms.references | K. Gunaratnam, C. Vidal, R. Boadle, C. Thekkedam, G. Duque, Mechanisms of palmitate-induced cell death in human osteoblasts, Biology open 2 (12) (2013) 1382–1389. | eng |
| dcterms.references | A.G. Veldhuis-Vlug, C.J. Rosen, Clinical implications of bone marrow adiposity, J. Intern. Med. 283 (2) (2018) 121–139. | eng |
| dcterms.references | L.F. Bonewald, The amazing osteocyte, J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 26 (2) (2011) 229–238. | eng |
| dcterms.references | L.F. Bonewald, Osteocytes as dynamic multifunctional cells, Ann. N. Y. Acad. Sci. 1116 (2007) 281–290. | eng |
| dcterms.references | R.S. Weinstein, S.C. Manolagas, Apoptosis and osteoporosis, Am. J. Med. 108 (2) (2000) 153–164. | eng |
| dcterms.references | S.C. Manolagas, A.M. Parfitt, What old means to bone, Trends Endocrinol Metab 21 (6) (2010) 369–374. | eng |
| dcterms.references | L.I. Plotkin, Apoptotic osteocytes and the control of targeted bone resorption, Current osteoporosis reports 12 (1) (2014) 121–126. | eng |
| dcterms.references | G. Gu, M. Mulari, Z. Peng, T.A. Hentunen, H.K. Vaananen, Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption, Biochem. Biophys. Res. Commun. 335 (4) (2005) 1095–1101. | eng |
| dcterms.references | O.D. Kennedy, M.B. Schaffler, The roles of osteocyte signaling in bone, J. Am. Acad. Orthop. Surg. 20 (10) (2012) 670–671. | eng |
| dcterms.references | H.M. Frost, Tetracycline-based histological analysis of bone remodeling, Calcif. Tissue Res. 3 (3) (1969) 211–237. | eng |
| dcterms.references | R.H. Unger, L. Orci, Lipoapoptosis: its mechanism and its diseases, Biochim. Biophys. Acta 1585 (2–3) (2002) 202–212. | eng |
| dcterms.references | L. Martino, M. Masini, M. Novelli, P. Beffy, M. Bugliani, L. Marselli, P. Masiello, P. Marchetti, V. De Tata, Palmitate activates autophagy in INS-1E beta-cells and in isolated rat and human pancreatic islets, PLoS One 7 (5) (2012) e36188. | eng |
| dcterms.references | T. Nakashima, M. Hayashi, T. Fukunaga, K. Kurata, M. Oh-Hora, J.Q. Feng, L.F. Bonewald, T. Kodama, A. Wutz, E.F. Wagner, J.M. Penninger, H. Takayanagi, Evidence for osteocyte regulation of bone homeostasis through RANKL expression, Nat. Med. 17 (10) (2011) 1231–1234. | eng |
| dcterms.references | A. Elbaz, X. Wu, D. Rivas, J.M. Gimble, G. Duque, Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro, J. Cell. Mol. Med. 14 (4) (2010) 982–991. | eng |
| dcterms.references | H.M. Davis, R. Pacheco-Costa, E.G. Atkinson, L.R. Brun, A.R. Gortazar, J. Harris, M. Hiasa, S.A. Bolarinwa, T. Yoneda, M. Ivan, A. Bruzzaniti, T. Bellido, L.I. Plotkin, Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging, Aging Cell 16 (3) (2017) 551–563. | eng |
| dcterms.references | L.F. Bonewald, Establishment and characterization of an osteocyte-like cell line, MLO-Y4, J. Bone Miner. Metab. 17 (1) (1999) 61–65. | eng |
| dcterms.references | M.K. Sutherland, J.C. Geoghegan, C. Yu, E. Turcott, J.E. Skonier, D.G. Winkler, J.A. Latham, Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation, Bone 35 (4) (2004) 828–835. | eng |
| dcterms.references | M.M. McDonald, A. Morse, A. Schindeler, K. Mikulec, L. Peacock, T. Cheng, J. Bobyn, L. Lee, P.A. Baldock, P.I. Croucher, P.P.L. Tam, D.G. Little, Homozygous Dkk1 knockout mice exhibit high bone mass phenotype due to increased bone formation, Calcif. Tissue Int. 102 (1) (2018) 105–116. | eng |
| dcterms.references | L.I. Plotkin, R.S. Weinstein, A.M. Parfitt, P.K. Roberson, S.C. Manolagas, T. Bellido, Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin, J. Clin. Invest. 104 (10) (1999) 1363–1374. | eng |
| dcterms.references | M. Almeida, L. Han, M. Martin-Millan, L.I. Plotkin, S.A. Stewart, P.K. Roberson, S. Kousteni, C.A. O'Brien, T. Bellido, A.M. Parfitt, R.S. Weinstein, R.L. Jilka, S.C. Manolagas, Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids, J. Biol. Chem. 282 (37) (2007) 27285–27297. | eng |
| dcterms.references | R.S. Weinstein, R.L. Jilka, A.M. Parfitt, S.C. Manolagas, Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone, J. Clin. Invest. 102 (2) (1998) 274–282. | eng |
| dcterms.references | O. Verborgt, G.J. Gibson, M.B. Schaffler, Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo, J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 15 (1) (2000) 60–67. | eng |
| dcterms.references | R. Deshimaru, K. Ishitani, K. Makita, F. Horiguchi, S. Nozawa, Analysis of fatty acid composition in human bone marrow aspirates, The Keio journal of medicine 54 (3) (2005) 150–155. | eng |
| dcterms.references | J.F. Griffith, D.K. Yeung, A.T. Ahuja, C.W. Choy, W.Y. Mei, S.S. Lam, T.P. Lam, Z.Y. Chen, P.C. Leung, A study of bone marrow and subcutaneous fatty acid composition in subjects of varying bone mineral density, Bone 44 (6) (2009) 1092–1096. | eng |
| dcterms.references | Y. Tsujimoto, S. Shimizu, Another way to die: autophagic programmed cell death, Cell Death Differ. 12 (Suppl. 2) (2005) 1528–1534. | eng |
| dcterms.references | Y.S. Rajawat, Z. Hilioti, I. Bossis, Aging: central role for autophagy and the lysosomal degradative system, Ageing Res. Rev. 8 (3) (2009) 199–213. | eng |
| dcterms.references | F. Madeo, N. Tavernarakis, G. Kroemer, Can autophagy promote longevity? Nat. Cell Biol. 12 (9) (2010) 842–846. | eng |
| dcterms.references | V. Pierrefite-Carle, S. Santucci-Darmanin, V. Breuil, O. Camuzard, G.F. Carle, Autophagy in bone: self-eating to stay in balance, Ageing Res. Rev. 24 (Pt B) (2015) 206–217. | eng |
| dcterms.references | M. Onal, M. Piemontese, J. Xiong, Y. Wang, L. Han, S. Ye, M. Komatsu, M. Selig, R.S. Weinstein, H. Zhao, R.L. Jilka, M. Almeida, S.C. Manolagas, C.A. O'Brien, Suppression of autophagy in osteocytes mimics skeletal aging, J. Biol. Chem. 288 (24) (2013) 17432–17440. | eng |
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