HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin
Open accessAbstract
Summary: HIV‐infected patients receiving antiretroviral therapy present an increased prevalence of age‐related comorbidities, including osteoporosis. HIV protease inhibitors ( PI s) have been suspected to participate to bone loss, but the mechanisms involved are unknown. In endothelial cells, some PI s have been shown to induce the accumulation of farnesylated prelamin‐ A , a biomarker of cell aging leading to cell senescence. Herein, we hypothesized that these PI s could induce premature aging of osteoblast precursors, human bone marrow mesenchymal stem cells ( MSC s), and affect their capacity to differentiate into osteoblasts. Senescence was studied in proliferating human MSC s after a 30‐day exposure to atazanavir and lopinavir with or without ritonavir. When compared to untreated cells, PI ‐treated MSC s had a reduced proliferative capacity that worsened with increasing passages. PI treatment led to increased oxidative stress and expression of senescence markers, including prelamin‐ A . Pravastatin, which blocks prelamin‐ A farnesylation, prevented PI ‐induced senescence and oxidative stress, while treatment with antioxidants partly reversed these effects. Moreover, senescent MSC s presented a decreased osteoblastic potential, which was restored by pravastatin treatment. Because age‐related bone loss is associated with increased bone marrow fat, we also evaluated the capacity of PI ‐treated MSC s to differentiate into adipocyte. We observed an altered adipocyte differentiation in PI ‐treated MSC s that was reverted by pravastatin. We have shown that some PI s alter osteoblast formation by affecting their differentiation potential in association with altered senescence in MSC s, with a beneficial effect of statin. These data corroborate the clinical observations and allow new insight into pathophysiological mechanisms of PI ‐induced bone loss in HIV ‐infected patients.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HIV proteins Tat and Nef and protease inhibitors lopinavir and atazanavir are capable of inducing senescence in BM-MSCs.
“These conflicts are possibly reconciled by reports that find both HIV proteins Tat and Nef and protease inhibitors lopinavir and atazanavir are capable of inducing senescence in BM‐MSCs.”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Hernandez‐Vallejo et al, 2013
Senescent BM-MSCs do not effectively differentiate into osteoblasts and deposit reduced calcium in vitro.
“Importantly, senescent BM‐MSCs do not be effectively differentiated into osteoblasts and deposit reduced levels of calcium in vitro (Hernandez‐Vallejo et al, 2013; Beaupere et al, 2015).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Hernandez‐Vallejo et al, 2013
Cites
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · see citing works
Carr, A. D., Samaras, K., Þórisdóttir, A. S., Kaufmann, G. R., Chisholm, D. J., & Cooper, D. A. (1999) · The Lancet · doi:10.1016/s0140-6736(98)08468-2 · Cited by 1,490 · see citing works
Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review
Brown, T. T., & Qaqish, R. B. (2006) · AIDS · doi:10.1097/qad.0b013e32801022eb · Cited by 924 · see citing works
Zhou, S., Greenberger, J. S., Epperly, M. W., Goff, J. P., Adler, C., LeBoff, M. S., & Glowacki, J. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00377.x · Cited by 782 · see citing works
Almeida, M., Li, H., Martín-Millán, M., O’Brien, C. A., & Manolagas, S. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702811200 · Cited by 546 · see citing works
Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing
Scaffidi, P., & Misteli, T. (2008) · Nature Cell Biology · doi:10.1038/ncb1708 · Cited by 500 · see citing works
Triant, V. A., Brown, T. T., Lee, H., & Grinspoon, S. K. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0828 · Cited by 489 · see citing works
Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis
Verma, S., Rajaratnam, J. H., Denton, J., Hoyland, J. A., & Byers, R. J. (2002) · Journal of Clinical Pathology · doi:10.1136/jcp.55.9.693 · Cited by 424 · see citing works
Varela, I., Pereira, S., Ugalde, A. P., Navarro, C. L., Suárez, M. F., Cau, P., Cadiñanos, J., Osorio, F. G., Foray, N., Cobo, J. L., et al. (2008) · Nature Medicine · doi:10.1038/nm1786 · Cited by 403 · see citing works
Capell, B. C., Erdos, M. R., Madigan, J. P., Fiordalisi, J. J., Varga, R., Conneely, K. N., Gordon, L. B., Der, C. J., Cox, A. D., & Collins, F. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506001102 · Cited by 395 · see citing works
NUTTALL, M. E. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.03.002 · Cited by 366 · see citing works
Mallon, P. W. G., Miller, J., Cooper, D. A., & Carr, A. D. (2003) · AIDS · doi:10.1097/00002030-200305020-00005 · Cited by 313 · see citing works
Drug-induced Osteoporosis: Mechanisms and Clinical Implications
Mazziotti, G., CANALIS, E. M., & Giustina, A. (2010) · The American Journal of Medicine · doi:10.1016/j.amjmed.2010.02.028 · Cited by 259 · see citing works
Duvivier, C., Kolta, S., Assoumou, L., Ghosn, J., Rozenberg, S., Murphy, R. L., Katlama, C., & Costagliola, D. G. (2009) · AIDS · doi:10.1097/qad.0b013e328328f789 · Cited by 239 · see citing works
Caron, M., Auclair, M., Donadille, B., Béréziat, V, Guerci, B., Laville, M., Narbonne, H., Bodemer, C., Lascols, O., Capeau, J., et al. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402197 · Cited by 226 · cited 7× · see citing works
“The inhibition of ZMP-STE24 by RTV and LPV results in permanently farnesylated prelamin-A, which has been shown to induce cell senescence (Caron et al., 2007; Coffinier et al., 2007).”
BackgroundMethodInfluentialSelf-citationContinuous antiretroviral therapy decreases bone mineral density
Grund, B., Peng, G., Gibert, C. L., Hoy, J., Isaksson, R., Shlay, J. C., Martínez, E., Reiss, P., Visnegarwala, F., & Carr, A. D. (2009) · AIDS · doi:10.1097/qad.0b013e32832c1792 · Cited by 212 · see citing works
Kim, M. J., Kim, C., Choi, Y. S., Kim, M., Park, C., & Suh, Y. (2012) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2012.03.014 · Cited by 207 · see citing works
Arnulf, B., Lecourt, S., Soulier, J., Ternaux, B., Lacassagne, M.-N., Crinquette, A., Dessoly, J., Sciaini, A.-K., Benbunan, M., Chomienne, C., et al. (2007) · Leukemia · doi:10.1038/sj.leu.2404466 · Cited by 190 · see citing works
Self-citationLagathu, C., Eustace, B. K., Prot, M., Frantz, D., Gu, Y., Bastard, J., Maachi, M., Azoulay, S., Briggs, M., Caron, M., et al. (2007) · Antiviral Therapy · doi:10.1177/135965350701200407 · Cited by 185 · see citing works
Self-citationHIV-associated lipodystrophy: from fat injury to premature aging
Caron, M., Lagathu, C., Boccara, F., Vigouroux, C., & Capeau, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.002 · Cited by 184 · see citing works
Self-citationSelect HIV Protease Inhibitors Alter Bone and Fat Metabolism ex Vivo
Jain, R. G., & Lenhard, J. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200069200 · Cited by 136 · see citing works
Coffinier, C., Hudon, S. E., Farber, E., Chang, S. Y., Hrycyna, C. A., Young, S. G., & Fong, L. G. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704212104 · Cited by 130 · see citing works
Brown, T. T., Ruppe, M. D., Kassner, R., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031506 · Cited by 122 · see citing works
Capeau, J. (2011) · Clinical Infectious Diseases · doi:10.1093/cid/cir628 · Cited by 119 · see citing works
Self-citationHuang, J. S., Rietschel, P., Hadigan, C. M., Rosenthal, D. I., & Grinspoon, S. K. (2001) · AIDS · doi:10.1097/00002030-200105250-00005 · Cited by 118 · see citing works
Effect of Lamin A/C Knockdown on Osteoblast Differentiation and Function
Akter, R., Rivas, D., Geneau, G., Drissi, H., & Duque, G. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.081010 · Cited by 118 · see citing works
McComsey, G. A., Kitch, D. W., Sax, P. E., Tebas, P., Tierney, C., Jahed, N. C., Myers, L., Melbourne, K., Ha, B., & Daar, E. S. (2011) · Clinical Infectious Diseases · doi:10.1093/cid/cir324 · Cited by 113 · see citing works
Bruedigam, C., Eijken, M., Koedam, M., van de Peppel, J., Drabek, K., Chiba, H., & van Leeuwen, J. P. T. M. (2010) · Stem Cells · doi:10.1002/stem.405 · Cited by 77 · see citing works
Lefèvre, C., Auclair, M., Boccara, F., Bastard, J.-P., Capeau, J., Vigouroux, C., & Caron-Debarle, M. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.110.213603 · Cited by 77 · see citing works
Self-citationVernochet, C., Azoulay, S., Duval, D., Guedj, R., Cottrez, F., Vidal, H., Ailhaud, G. P., & Dani, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408687200 · Cited by 75 · see citing works
Stable Bone Density in HAART-Treated Individuals with HIV: A Meta-Analysis
Bolland, M. J., Wang, T. K. M., Grey, A. B., Gamble, G. D., & Reid, I. R. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0591 · Cited by 73 · see citing works
Stone, B., Dockrell, D. H., Bowman, C., & McCloskey, E. V. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.07.029 · Cited by 69 · see citing works
Hansen, A. E., Obel, N., Nielsen, H. I., Pedersen, C. D., & Gerstoft, J. (2010) · HIV Medicine · doi:10.1111/j.1468-1293.2010.00864.x · Cited by 64 · see citing works
Rejnmark, L., Vestergaard, P., & Mosekilde, L. (2006) · Calcified Tissue International · doi:10.1007/s00223-006-0024-4 · Cited by 52 · see citing works
Osteoporosis and Bone Health in HIV
Powderly, W. G. (2012) · Current HIV/AIDS Reports · doi:10.1007/s11904-012-0119-7 · Cited by 51 · see citing works
Statins: under investigation for increasing bone mineral density and augmenting fracture healing
Tang, Q. O., Tran, G. T., Gamie, Z., Graham, S. M., Tsialogiannis, E., Tsiridis, E., Linder, T., & Tsiridis, E. E. (2008) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.17.10.1435 · Cited by 51 · see citing works
HIV Type 1 Alters Mesenchymal Stem Cell Differentiation Potential and Cell Phenotype ex Vivo
Cotter, E. J., Chew, N., Powderly, W. G., & Doran, P. (2010) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2010.0114 · Cited by 50 · see citing works
Accelerated Features of Age-Related Bone Loss in Zmpste24 Metalloproteinase-Deficient Mice
Rivas, J. D. L., Li, W., Akter, R., Henderson, J. E., & Duque, G. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/glp089 · Cited by 48 · see citing works
de Eguino, G. R., Infante, A., Schlangen, K., Aransay, A. M., Fullaondo, A., Soriano‐Navarro, M., García‐Verdugo, J. M., Martín, Á. G., & Rodrı́guez, C. I. (2012) · Stem Cells Translational Medicine · doi:10.5966/sctm.2011-0010 · Cited by 40 · see citing works
Reduced intravertebral bone marrow fat in HIV-infected men
Huang, J. S., Mulkern, R. V., & Grinspoon, S. K. (2002) · AIDS · doi:10.1097/00002030-200206140-00009 · Cited by 39 · see citing works
Carr, A. D., Ritzhaupt, A., Zhang, W., Zajdenverg, R., Workman, C., Gatell, J. M., Cahn, P. E., & Chaves, R. L. (2008) · AIDS · doi:10.1097/qad.0b013e328315a7a5 · Cited by 35 · see citing works
Bone turnover markers in HIV disease.
Haskelberg, H., Carr, A. D., & Emery, S. (2012) · PubMed · Cited by 32 · see citing works
Dynamics of Lamin-A Processing Following Precursor Accumulation
Liu, Q., Kim, D. I., Syme, J., Luvalle, P. A., Burke, B. E., & Roux, K. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010874 · Cited by 26 · see citing works
Naito, M., Omoteyama, K., Mikami, Y., Takagi, M., & Takahashi, T. (2011) · Histochemistry and Cell Biology · doi:10.1007/s00418-011-0890-3 · Cited by 18 · see citing works
Iwasaki, Y., Yamato, H., & Fukagawa, M. (2011) · Therapeutic Apheresis and Dialysis · doi:10.1111/j.1744-9987.2010.00888.x · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A proteomic atlas of senescence-associated secretomes for aging biomarker development
Basisty, N., Kale, A., Jeon, O. H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., Ferrucci, L., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000599 · Cited by 1,348 · see citing works
Beaupere, C., Garcia, M., Larghero, J., Fève, B., Capeau, J., & Lagathu, C. (2015) · Aging Cell · doi:10.1111/acel.12308 · Cited by 85 · see citing works
Self-citationBasisty, N., Kale, A., Patel, S., Campisi, J., & Schilling, B. (2020) · Expert Review of Proteomics · doi:10.1080/14789450.2020.1766976 · Cited by 69 · see citing works
Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration
Rai, M., Curley, M., Coleman, Z., & Demontis, F. (2022) · Aging Cell · doi:10.1111/acel.13603 · Cited by 72 · see citing works
Astrocyte senescence and metabolic changes in response to HIV antiretroviral therapy drugs
Cohen, J., D’Agostino, L., Wilson, J., Tuzer, F., & Torres, C. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00281 · Cited by 58 · see citing works
The struggle of a good friend getting old: cellular senescence in viral responses and therapy
Kohli, J., Veenstra, I., & Demaria, M. (2021) · The EMBO Reports · doi:10.15252/embr.202052243 · Cited by 52 · see citing works
Auclair, M., Afonso, P., Capel, E., Caron-Debarle, M., & Capeau, J. (2014) · Antiviral Therapy · doi:10.3851/imp2752 · Cited by 42 · see citing works
Self-citation
- Authors
- Hernandez‐Vallejo, S. J., Beaupere, C., Larghero, J., Capeau, J., & Lagathu, C.
- Affiliations
- INSERM UMRS938 Paris France
- Cell Therapy Unit Hôpital Saint Louis Paris France
- Inserm (FR)
- Corresponding author
- Lagathu, Claire
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2013-07-19
- Volume
- 12
- Issue
- 6
- Pages
- 955-965
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- OpenAlex
- W2134828479
- Cited by
- 70
- References
- 45
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 11 · 2013: 1
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- HIV protease inhibitors, bone marrow mesenchymal stem cells, cellular senescence, osteogenic differentiation, pravastatin, atazanavir, lopinavir, ritonavir, oxidative stress, osteoporosis, bone loss, adipogenesis, statins, HIV-associated bone loss
- MeSH terms
- Atazanavir Sulfate, Antioxidants, Bone Marrow Cells, Cell Differentiation, Humans, Oligopeptides, Osteoblasts, Pyridines, Cellular Senescence, Pravastatin, HIV Protease Inhibitors, Oxidative Stress, Cell Proliferation, Adipogenesis, Mesenchymal Stem Cells, Lopinavir
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
