Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

Gómez‐Santos, Beatriz; Urturi, Diego Sáenz de; Núñez-García, Maitane; González-Romero, Francisco; Buqué, Xabier; Aurrekoetxea, Igor; Juan, Virginia Gutiérrez de; Gonzalez-Rellan, María J.; García‐Monzón, Carmelo; González-Rodrı́guez, Águeda; Mosteiro, Lorena; Errazti, Gaizka; Mifsut, Patricia; Gaztambide, Sonia; Castaño, Luís; Martín, César San; Nogueiras, Rubén; Martínez‐Chantar, María Luz; Syn, Wing–Kin; Aspichueta, Patricia

doi:10.1111/acel.13183

Cited by 22 publications

(17 citation statements)

References 53 publications

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“…Our in vivo results from HFD-challenged mice and in vitro evidence from cultured preosteoclasts showed that senescent preosteoclasts secrete previously identified common SASP factors, such as IL-1β, IL-6, VEGF, and OPN (32,(68)(69)(70), as well as several factors that were not previously recognized in SnCs, including Lipocalin-2, Resistin, Cystatin C, IL-33, CCN4, MPO, and PDGF-BB. Importantly, the abnormally high production of these factors in the subchondral bone of HFDchallenged mice is fully or partially rectified by deletion of p16 from preosteoclasts.…”

Section: Discussionsupporting

confidence: 52%

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Wan

Liu

et al. 2022

Preprint

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Background: Metabolic syndrome–associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA. Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system. Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal anti-inflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA. Conclusions: Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential. Funding: This work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to M.W., R01AR079620 to S.D., and P01AG066603 to X.C.

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Section: Discussionsupporting

confidence: 52%

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Wan

Liu

et al. 2022

Preprint

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“…( 36 ) OPN plays a role in the progression of nonalcoholic steatohepatitis (NASH) by inhibiting autophagy ( 37 ) and increasing hepatocyte senescence. ( 38 )…”

Section: Opn and Hepatic Steatosismentioning

confidence: 99%

Osteopontin Takes Center Stage in Chronic Liver Disease

et al. 2021

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Osteopontin (OPN) was first identified in 1986. The prefix osteo‐ means bone; however, OPN is expressed in other tissues, including liver. The suffix ‐pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well‐established physiological roles, multiple “omics” analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non‐alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.

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“…ER stress is also involved in the progression of senescence in osteoarthritic chondrocytes, accompanied by increased SA-β-galactosidase activity [151]. A recent study in mice and patients showed that NAFLD was associated with increased expression of senescence markers in the liver, and that senescence correlated with increased lipid accumulation and increased ER stress, demonstrated by increased phosphorylation of eIF2a and IRE1a [152]. Therefore, ER stress is very likely to contribute to the induction of cellular senescence during NAFLD.…”

Section: Senescence and Er Stressmentioning

confidence: 99%

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease

et al. 2022

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Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD.

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Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 22 publications

References 53 publications

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Osteopontin Takes Center Stage in Chronic Liver Disease

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease

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