Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
Open accessAbstract
BACKGROUND: Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy. METHODS: Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-β-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration. FINDINGS: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. INTERPRETATION: These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment. FUND: This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovación y Universidades, Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Economía y Competitividad, by grants of the National Instiutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank FOREUM Foundation for Research in Rheumatology for their support.
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Written from the paper’s full text.
TL;DR
A high-throughput screen of approved drugs in human chondrocytes identified fenofibrate, a PPARα agonist, as a dual senolytic and pro-autophagic compound that protects against cartilage degradation in preclinical models. Retrospective OAI cohort data suggest fibrate use is associated with improved WOMAC function and total scores in knee OA patients.
Key findings
- From the Prestwick Chemical Library of 1120 approved drugs, 279 compounds decreased IL-6-induced chondrocyte senescence; 14 of these also increased autophagic flux. Fenofibrate (FN) reduced SA-β-Gal activity and increased autophagic flux in IL-6-treated chondrocytes.
- PPARα agonists acted as senolytics by selectively inducing apoptosis in senescent chondrocytes: FN showed a dose-dependent senolytic effect, GW7647 was toxic at 50 μM, and CP775146 was senolytic only at 12.5 μM. FN also reduced p21, p16, NF-κB/RELA, and phospho-S6 while increasing LC3 in OA and ageing primary human chondrocytes; PPARα knockdown increased p21 and NF-κB/RELA and reduced FOXO1.
- FN reduced proteoglycan loss in human cartilage explants treated with IL-1β and reduced nitric oxide production. PPARα expression was decreased with ageing and OA in mouse cartilage and in blood and cartilage from knee OA patients.
- In the Osteoarthritis Initiative cohort, 35 fibrate users were matched to 35 controls; fibrate use-by-time interaction was associated with an average yearly decrease in WOMAC function grade by 1.15 and WOMAC total score by 1.6, with a trend toward decreased WOMAC pain. There were 3 total knee replacements (4.3% of knees) in fibrate users versus 7 (11.4% of knees) in matched controls.
Methods
- Primary screening used T/C28a2 human chondrocytes treated with IL-6 (20 ng/ml) plus the Prestwick Chemical Library (1120 compounds, 10 μM) for 72 h, with C12FDG-based SA-β-Gal imaging. Secondary screening used mCherry-EGFP-LC3 T/C28a2 chondrocytes treated with IL-6 plus 279 hit compounds for 18 h, measuring autophagic flux by mCherry/EGFP ratio.
- Validation used primary human OA chondrocytes (mean ± SD: 76.8 ± 4.71 years, n = 5), normal-ageing chondrocytes (76.1 ± 14.50 years, n = 10), human cartilage explants (73.33 ± 17.95 years, n = 3), mouse ageing and surgically induced OA models, and blood/cartilage from the PROCOAC cohort (non-OA n = 25; knee OA n = 30). Analyses included qRT-PCR, Western blotting, immunohistochemistry, Safranin O staining, nitric oxide assay, and flow cytometry.
- The OAI analysis used longitudinal data from progression and incidence subcohorts; 35 fibrate users and 3322 non-users were identified, then 35 users were matched 1:1 to 35 controls using genetic matching. Generalized estimating equations modeled outcomes over time with a user*time interaction term.
Limitations
- The paper states that the OAI clinical analysis had a small sample size, which may have reduced statistical power for detecting pain reduction, and that the dissociation between fibrate effects on disability and pain is difficult to interpret. It also states that further prospective and conclusive studies are needed.
- The paper notes that a prior OAI analysis used a prevalent-user design that may be associated with bias; this study used a new-user design but remains an observational, retrospective analysis, so residual confounding cannot be excluded.
- Evident from the text: the mechanistic screen relies on IL-6-induced senescence in the T/C28a2 chondrocyte line, and much of the preclinical validation uses mouse models and ex vivo human cartilage; direct causal proof in human OA cartilage in vivo is not provided.
Model-written summary. Check it against the paper before relying on it.
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- Findingown data
IL-6 induced a significant increase in overall SA-β-Gal activity in human chondrocytes.
“IL-6 induced a significant increase in both the percentage of cells positive for in SA-β-Gal activity at 72 h (Fig. 1b) and overall SA-β-Gal activity.”
Quote in the paperSubstantial claim - Findingown data
PPARα expression is reduced in blood and cartilage from knees of osteoarthritis patients.
“also in blood and cartilage from knees of OA patients”
- Also stated in: § Introduction · plain
“also in blood and cartilage from knees of OA patients”
Quote in the paperSubstantial claim- Rests on an assumption: PPARα expression in blood is a valid proxy for PPARα expression in cartilage and for osteoarthritis status.
- Also stated in: § Introduction · plain
- Findingown data
Fenofibrate protects against cartilage degradation.
“protected against cartilage degradation”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Findingown data
PPARα expression is reduced through ageing and osteoarthritis in mice.
“PPARα expression was reduced through both ageing and OA in mice”
- Also stated in: § Introduction · boosted
“We also demonstrate that PPARα expression in mice was reduced due to ageing or OA”
Quote in the paperSubstantial claim - Also stated in: § Introduction · boosted
- Findingown data
IL-6 induced a significant decrease in autophagic flux at 18 h in human chondrocytes.
“Similarly, IL-6 induced a significant decrease in autophagic flux as well as the percent of cells positive for autophagy at 18 h (Fig. 1c).”
Quote in the paperSubstantial claim
- Findingown data
IL-6 induced a significant increase in the percentage of cells positive for SA-β-Gal activity at 72 h in human chondrocytes.
“IL-6 induced a significant increase in both the percentage of cells positive for in SA-β-Gal activity at 72 h (Fig. 1b) and overall SA-β-Gal activity.”
Quote in the paperSubstantial claim - Findingown data
IL-6 induced a significant decrease in the percent of cells positive for autophagy at 18 h in human chondrocytes.
“Similarly, IL-6 induced a significant decrease in autophagic flux as well as the percent of cells positive for autophagy at 18 h (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Fenofibrate increases autophagy in both ageing human and osteoarthritis chondrocytes.
“increased autophagy in both ageing human and OA chondrocytes”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Findingown data
PPARα knockdown confers the opposite effect to fenofibrate on senescence, inflammation and autophagy in chondrocytes.
“PPARα knockdown conferred the opposite effect”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Findingown data
Senotherapeutic molecules with pro-autophagic activity were identified.
“Senotherapeutic molecules with pro-autophagic activity were identified.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Findingown data
Fenofibrate reduces the number of senescent cells via apoptosis.
“Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Findingown data
Fenofibrate increases autophagic flux.
“increased autophagic flux”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Findingnone given
In a retrospective study, fibrate treatment improved osteoarthritis clinical conditions in human patients from the Osteoarthritis Initiative Cohort.
“in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort.”
Quote in the paperSubstantial claim- Rests on an assumption: The association between fibrate treatment and improved osteoarthritis clinical conditions in the retrospective Osteoarthritis Initiative cohort is not confounded.
- Findingown data
CP775146 was senolytic only at 12.5 μM in human chondrocytes.
“CP775146 was senolytic only at 12.5 μM (Fig. 4c)”
Quote in the paperNot a substantial claim - Findingown data
FN showed a dose-dependent senolytic effect in human chondrocytes.
“FN showed a dose-dependent senolytic effect (Fig. 4a)”
Quote in the paperSubstantial claim - Findingown data
14 compounds from the 279 increased autophagic flux in human chondrocytes.
“From this set of 279, 14 compounds also increased autophagic flux and were selected as dual senescence and autophagy modulators for confirmatory studies (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Only FN increased autophagic flux at both 10 and 50 μM in human chondrocytes.
“Only FN increased autophagic flux at both concentrations while the other PPARα agonists showed lower and mostly non-significant effects.”
Quote in the paperSubstantial claim - Findingown data
Genetic deletion of PPARα increased NF-κB/RELA expression levels.
“Remarkably, genetic deletion of PPARα promoted senescence and SASP/inflammation by increasing p21 and NF-κB/RELA expression levels respectively as well as increased LC3 and reduced FOXO1 expression (Fig. 7e-i).”
Quote in the paperSubstantial claim - Findingown data
Genetic deletion of PPARα reduced FOXO1 expression.
“Remarkably, genetic deletion of PPARα promoted senescence and SASP/inflammation by increasing p21 and NF-κB/RELA expression levels respectively as well as increased LC3 and reduced FOXO1 expression (Fig. 7e-i).”
Quote in the paperNot a substantial claim - Findingown data
In ageing chondrocytes, FN reduced the level of phospho-S6.
“In ageing chondrocytes FN, reduced expression of p16, p21 and NFκB/RELA and increased expression of LC3 while reducing the level of phospho-S6 (Fig. 7d).”
Quote in the paperSubstantial claim - Findingown data
In ageing chondrocytes, FN reduced expression of p21.
“In ageing chondrocytes FN, reduced expression of p16, p21 and NFκB/RELA and increased expression of LC3 while reducing the level of phospho-S6 (Fig. 7d).”
Quote in the paperSubstantial claim - Findingown data
FN treatment did not induce cell death in primary non-senescent human chondrocytes.
“Moreover, FN treatment did not induce cell death in primary non-senescent human chondrocytes (Supplementary Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
In ageing chondrocytes, FN increased expression of LC3.
“In ageing chondrocytes FN, reduced expression of p16, p21 and NFκB/RELA and increased expression of LC3 while reducing the level of phospho-S6 (Fig. 7d).”
Quote in the paperSubstantial claim - Findingown data
Fenofibrate (FN) significantly reduced SA-β-Gal activity in IL-6 treated chondrocytes at 72 h.
“Fenofibrate (FN), a PPARα agonist significantly reduced SA-β-Gal activity in IL-6 treated chondrocytes at 72 h (Fig. 3a) and this was accompanied by an increase in autophagic flux at 18 h (Fig. 3b), confirming its senotherapeutic and autophagy promoting activity.”
Quote in the paperSubstantial claim - Findingown data
IL-6 stimulation significantly increased phospho-ribosomal S6 (prbS6) levels in human chondrocytes.
“In addition, p21, an important senescence marker [49] and phospho-ribosomal S6 (prbS6), a direct target of the mammalian target of rapamycin (mTOR) [50], were significantly increased after IL-6 stimulation (Supplementary Fig. 3).”
Quote in the paperNot a substantial claim - Findingown data
In OA chondrocytes, FN reduced phospho-S6.
“In OA chondrocytes, FN reduced expression of p21 and the NF-κB p65 subunit RELA (Fig. 7c) and reduced phosphor-S6.”
Quote in the paperSubstantial claim - Findingown data
The compounds identified primarily targeted ion channels and hormone receptors related to metabolism.
“The compounds identified primarily targeted ion channels and hormone receptors related to metabolism (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
FN showed similar effects to navitoclax in human chondrocytes.
“FN showed similar effects to navitoclax (a reference control for senolytic activity)”
Quote in the paperSubstantial claim - Findingown data
Rapamycin did not increase apoptosis in human chondrocytes.
“while the senomorphic drug rapamycin did not increase apoptosis”
Quote in the paperSubstantial claim - Findingown data
In OA chondrocytes, FN reduced expression of p21.
“In OA chondrocytes, FN reduced expression of p21 and the NF-κB p65 subunit RELA (Fig. 7c) and reduced phosphor-S6.”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists act as senolytics in senescent human IMR90 lung fibroblasts.
“The results showed that PPARα agonists act as senolytics in both models”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists reduced the number of senescent cells in human chondrocytes.
“The PPARα agonists showed senolytic activity in human chondrocytes by reducing both the number of senescent cells and total number of cells.”
Quote in the paperSubstantial claim - Findingown data
In ageing chondrocytes, FN reduced expression of p16.
“In ageing chondrocytes FN, reduced expression of p16, p21 and NFκB/RELA and increased expression of LC3 while reducing the level of phospho-S6 (Fig. 7d).”
Quote in the paperSubstantial claim - Findingown data
GW7647 was toxic at 50 μM in human chondrocytes.
“GW7647 was toxic at 50 μM (Fig. 4b)”
Quote in the paperNot a substantial claim - Findingown data
Genetic deletion of PPARα increased p21 expression levels.
“Remarkably, genetic deletion of PPARα promoted senescence and SASP/inflammation by increasing p21 and NF-κB/RELA expression levels respectively as well as increased LC3 and reduced FOXO1 expression (Fig. 7e-i).”
Quote in the paperSubstantial claim - Findingown data
FN treatment was correlated with a reduction of nitric oxide (NO) production.
“This protective role was correlated with a reduction of nitric oxide (NO) production (Fig. 7b).”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists reduced the total number of cells in human chondrocytes.
“The PPARα agonists showed senolytic activity in human chondrocytes by reducing both the number of senescent cells and total number of cells.”
Quote in the paperSubstantial claim - Findingown data
Genetic deletion of PPARα increased LC3 expression.
“Remarkably, genetic deletion of PPARα promoted senescence and SASP/inflammation by increasing p21 and NF-κB/RELA expression levels respectively as well as increased LC3 and reduced FOXO1 expression (Fig. 7e-i).”
Quote in the paperNot a substantial claim - Findingown data
In OA chondrocytes, FN reduced expression of the NF-κB p65 subunit RELA.
“In OA chondrocytes, FN reduced expression of p21 and the NF-κB p65 subunit RELA (Fig. 7c) and reduced phosphor-S6.”
Quote in the paperSubstantial claim - Findingown data
Fenofibrate (FN) increased autophagic flux at 18 h in IL-6 treated chondrocytes.
“Fenofibrate (FN), a PPARα agonist significantly reduced SA-β-Gal activity in IL-6 treated chondrocytes at 72 h (Fig. 3a) and this was accompanied by an increase in autophagic flux at 18 h (Fig. 3b), confirming its senotherapeutic and autophagy promoting activity.”
Quote in the paperSubstantial claim - Findingown data
IL-6 stimulation significantly increased p21 levels in human chondrocytes.
“In addition, p21, an important senescence marker [49] and phospho-ribosomal S6 (prbS6), a direct target of the mammalian target of rapamycin (mTOR) [50], were significantly increased after IL-6 stimulation (Supplementary Fig. 3).”
Quote in the paperNot a substantial claim - Findingown data
PPARα agonists increased FoxO1 gene expression at 8 and 24 h in human chondrocytes.
“In addition, PPARα agonists also increased LC3 and FoxO1 gene expression at 8 and 24 h (Fig. 6 b, c).”
Quote in the paperSubstantial claim - Findingown data
279 compounds from the Prestwick library decreased IL-6 induced senescence in human chondrocytes.
“Results showed that 279 compounds from the Prestwick library decreased IL-6 induced senescence (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists increased LC3 gene expression at 8 and 24 h in human chondrocytes.
“In addition, PPARα agonists also increased LC3 and FoxO1 gene expression at 8 and 24 h (Fig. 6 b, c).”
Quote in the paperSubstantial claim - Findingown data
In ageing chondrocytes, FN reduced expression of NFκB/RELA.
“In ageing chondrocytes FN, reduced expression of p16, p21 and NFκB/RELA and increased expression of LC3 while reducing the level of phospho-S6 (Fig. 7d).”
Quote in the paperSubstantial claim - Findingown data
Treatment with FN reduced proteoglycan loss in cartilage explants in response to IL-1β treatment.
“Treatment with FN reduced proteoglycan loss in cartilage explants and protected against cartilage degradation in response to IL-1β treatment (Fig. 7a).”
Quote in the paperSubstantial claim - Findingown data
Other PPARα agonists showed lower and mostly non-significant effects on autophagic flux in human chondrocytes.
“Only FN increased autophagic flux at both concentrations while the other PPARα agonists showed lower and mostly non-significant effects.”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists act as senolytics in DNA repair deficient Ercc1−/− MEFs fibroblasts.
“The results showed that PPARα agonists act as senolytics in both models”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists (10 and 50 μM) increased apoptosis in IL-6-treated chondrocytes.
“Quantification of apoptosis demonstrated that PPARα agonists (10 and 50 μM) selectively eliminated senescenct cells by increasing apoptosis following IL-6-mediated induction of senescence (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
PPARα deficient human chondrocytes showed increased expression of inflammation mediators.
“We found that PPARα deficient human chondrocytes were susceptible to senescence, increased expression of inflammation mediators and to changes in homeostasis by a reduction of FoxO1 expression and an increase in LC3”
Quote in the paperSubstantial claim - Findingown data
The cell-based screening assay yielded a number of drugs with different mechanisms of action potentially interacting with OA pathogenesis pathways.
“Our cell-based screening assay yielded a number of drugs with different mechanism of actions potentially interacting with OA pathogenesis pathways.”
Quote in the paperSubstantial claim - Findingown data
Treating OA and ageing chondrocytes with fenofibrate results in abrogation of the active, phosphorylated form of the mTOR effector S6 Ribosomal Protein.
“treating OA and ageing chondrocytes with fenofibrate results in abrogation of the active, phosphorylated form of the mTOR effector S6 Ribosomal Protein.”
Quote in the paperSubstantial claim - Findingown data
Fibrate use by time interaction was associated with a statistically significant improvement of WOMAC function and WOMAC total scores in human OA patients.
“the results indicate that fibrate use by time interaction was associated with a statistically significant improvement of WOMAC function and WOMAC total scores.”
- Also stated in: § Discussion · plain
“pharmacological activation of PPARα by fibrate treatment in human OA patients was associated with a significant decrease in progressive disability”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
During follow-up, fibrate users had fewer total knee replacements than matched controls (3 vs 7).
“during the follow-up there were 3 (4.3% of the knees) total knee replacements in the fibrate user group and 7 (11.4% of the knees) in the matched control group, respectively.”
- Also stated in: § Discussion · plain
“There were fewer joint replacement surgeries in patients taking fibrates.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
The number of PPARα-positive chondrocytes in knee cartilage significantly decreased with ageing in mice, with only a minimal percentage of cells positive for PPARα at 30 months.
“The number of PPARα-positive chondrocytes in knee cartilage significantly decreased with ageing, with only a minimal percentage of the cells positive for PPARα at 30 months (Fig. 9a).”
Quote in the paperSubstantial claim - Findingown data
FN treatment increased PPARα expression at both gene and protein level in human chondrocytes.
“FN treatment increased PPARα expression at both gene and protein level (Fig. 8a, b)”
Quote in the paperSubstantial claim - Findingcitation
PPARα ligands selectively eliminate senescent chondrocytes via cell death through apoptosis.
“Our results demonstrate that PPARα ligands selectively eliminate senescent chondrocytes via cell death through apoptosis [4].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] van Deursen J.M. The role of senescent cells in ageing Nature 509 7501 2014 439 446 24848057 PMC4214092 source
Not checked in the free run.
- Findingown data
PPARα agonists increased expression of CPT1A in human chondrocytes.
“The results showed an increase in expression of CPT1A expression, a target gene of PPARα [60], suggesting that these ligands regulate mitochondrial fatty acid β-oxidation in human chondrocytes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Xiao Y. Wang J. Yan W. Zhou K. Cao Y. Cai W. p38alpha MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure Cell Death Dis. 8 10 2017 e3110 29022907 PMC5682685 source
Not checked in the free run.
- Findingown data
In OA cartilage, PPARα positive cells were present only in chondrocyte clusters.
“in OA cartilage, PPARα positive cells were present only in the chondrocyte clusters (Fig. 10b, c).”
Quote in the paperNot a substantial claim - Findingown data
In human cartilage, PPARα was mainly expressed in the superficial zone in non-OA cartilage, with decreased expression in OA grade III-VI patients.
“immunohistochemical analysis of cartilage showed that PPARα was mainly expressed in the superficial zone in non-OA cartilage with decreased expression in OA grade III-VI patients.”
Quote in the paperSubstantial claim - Findingown data
Levels of PPARα were lower in blood from OA patients compared to non-OA controls.
“Levels of PPARα were lower in OA patients compared to non-OA controls (Fig. 10a).”
Quote in the paperSubstantial claim - Findingown data
In the surgical OA mouse model, 10 weeks after transection of the medial meniscotibial ligament and the medial collateral ligament, PPARα-positive cells were significantly reduced.
“In the surgical OA model, 10 weeks after transection of the medial meniscotibial ligament and the medial collateral ligament (MMTL+MCL), PPARα-positive cells were also significantly reduced (Fig. 9b).”
Quote in the paperSubstantial claim - Findingown data
PPARα deficient human chondrocytes were susceptible to senescence.
“We found that PPARα deficient human chondrocytes were susceptible to senescence, increased expression of inflammation mediators and to changes in homeostasis by a reduction of FoxO1 expression and an increase in LC3”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists induced autophagic flux, mediated by a related increase in cell homeostasis markers such as LC3 and FoxO1.
“PPARα agonists induced autophagic flux, mediated by a related increase in cell homeostasis markers, such as LC3 and FoxO1.”
Quote in the paperSubstantial claim - Findingown data
PPARα deficient human chondrocytes showed changes in homeostasis by a reduction of FoxO1 expression and an increase in LC3.
“We found that PPARα deficient human chondrocytes were susceptible to senescence, increased expression of inflammation mediators and to changes in homeostasis by a reduction of FoxO1 expression and an increase in LC3”
Quote in the paperSubstantial claim - Findingown data
The PPARα agonist fenofibrate significantly induced autophagic flux.
“Here, we have demonstrated that the PPARα agonist fenofibrate (FN) significantly reduced chondrocyte senescence and induced autophagic flux significantly, indicating a partial reversion of the chondrocyte age-related phenotype.”
Quote in the paperSubstantial claim - Findingown data
PPARα agonists regulated FA β-oxidation genes in human chondrocytes.
“PPARα agonists regulated FA β-oxidation genes in human chondrocytes (Fig. 8c, d).”
Quote in the paperSubstantial claim - Findingown data
There was a trend towards a decrease in WOMAC pain score with fibrate use.
“There was also a trend towards a decrease in WOMAC pain score.”
- Also stated in: § Discussion · hedged
“a trend towards a decrease in knee pain.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Findingown data
Fibrate use, compared with non-use, was associated with an average yearly decrease in WOMAC function grade by 1.15 and WOMAC total score by 1.6, as reflected by β-coefficients of 1.15 and 1.6.
“The results suggest that the fibrate use, when compared with non-use, was associated with an average yearly decrease in WOMAC function grade by 1.15 and WOMAC total score by 1.6, as reflected by β-coefficients of 1.15 and 1.6, respectively”
Quote in the paperSubstantial claim - Findingown data
The PPARα agonist fenofibrate significantly reduced chondrocyte senescence.
“Here, we have demonstrated that the PPARα agonist fenofibrate (FN) significantly reduced chondrocyte senescence and induced autophagic flux significantly, indicating a partial reversion of the chondrocyte age-related phenotype.”
Quote in the paperSubstantial claim - Premisecitation
Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis.
“Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA)”
- Also stated in: § Introduction · plain
“many chronic diseases such as osteoarthritis (OA) are associated with the hallmarks of ageing, including cellular senescence and defective autophagy [1]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Lopez-Otin C. Blasco M.A. Partridge L. Serrano M. Kroemer G. The hallmarks of aging Cell 153 6 2013 1194 1217 23746838 PMC3836174 source
Not checked in the free run.
- Also stated in: § Introduction · plain
- Premisecitation
Accumulation of senescent cells in tissues contributes to age-related diseases.
“Accumulation of senescent cells in tissues contributes to age-related diseases [[3], [4], [5], [6], [7]].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [3] Wang R. Yu Z. Sunchu B. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism Aging Cell 16 3 2017 564 574 28371119 PMC5418203 source
Not checked in the free run.
- cites [4] van Deursen J.M. The role of senescent cells in ageing Nature 509 7501 2014 439 446 24848057 PMC4214092 source
Not checked in the free run.
- cites [5] Baker D.J. Childs B.G. Durik M. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan Nature 530 7589 2016 184 189 26840489 PMC4845101 source
Not checked in the free run.
- Interpretationreasoning
Fibrate drugs could have immediate clinical utility for age-related cartilage degeneration and osteoarthritis treatment.
“Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment.”
Quote in the paperSubstantial claim- Rests on an assumption: The association between fibrate treatment and improved osteoarthritis clinical conditions in the retrospective Osteoarthritis Initiative cohort is not confounded.
- Rests on an assumption: PPARα expression in blood is a valid proxy for PPARα expression in cartilage and for osteoarthritis status.
- Premisecitation
Pharmacological activation of autophagy with small molecules has shown efficacy in preclinical models of osteoarthritis.
“pharmacological activation of autophagy with small molecules has shown efficacy in preclinical models of OA [20]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Vinatier C. Dominguez E. Guicheux J. Carames B. Role of the inflammation-autophagy-senescence integrative network in osteoarthritis Front. Physiol. 9 2018 706 29988615 PMC6026810 source
Not checked in the free run.
- Premisecitation
Deficient autophagy is linked with cartilage ageing and osteoarthritis.
“There is strong evidence linking deficient autophagy, essential for cellular homeostasis, with cartilage ageing and OA [21,22].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Carames B. Taniguchi N. Otsuki S. Blanco F.J. Lotz M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis Arthritis Rheum. 62 3 2010 791 801 20187128 PMC2838960 source
Not checked in the free run.
- cites [22] Carames B. Olmer M. Kiosses W.B. Lotz M.K. The relationship of autophagy defects to cartilage damage during joint aging in a mouse model Arthrit. Rheumatol. (Hoboken, NJ) 67 6 2015 1568 1576 PMC4446178 25708836 source
Not checked in the free run.
- Premisecitation
Selective clearance of senescent chondrocytes using the Bcl-2 family inhibitor Navitoclax has beneficial effects in animal models of osteoarthritis.
“A major step into the translation of senolytic treatments for OA was demonstrated by the beneficial effects of selective clearance of senescence chondrocytes using the Bcl-2 family inhibitor Navitoclax in animal models [14].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Jeon O.H. Kim C. Laberge R.M. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment Nat. Med. 23 6 2017 775 781 28436958 PMC5785239 source
Not checked in the free run.
- Interpretationown data
The data establish strong preclinical evidence that could lead to development of novel disease-modifying therapies targeting lipid metabolism to prevent and treat osteoarthritis.
“Collectively, our data establish strong preclinical evidence that could lead to the development of novel disease-modifying therapies targeting lipid metabolism to prevent and treat OA.”
Quote in the paperSubstantial claim- Rests on an assumption: The association between fibrate treatment and improved osteoarthritis clinical conditions in the retrospective Osteoarthritis Initiative cohort is not confounded.
- Rests on an assumption: PPARα expression in blood is a valid proxy for PPARα expression in cartilage and for osteoarthritis status.
- Interpretationreasoning
Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent detrimental microenvironment changes in joint dysfunction.
“Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent the detrimental microenvironment changes occurring in joint dysfunction.”
Quote in the paperSubstantial claim - Interpretationown data
Activating PPARα initiates a transcriptional program that enhances chondrocyte homeostasis.
“Our data provides compelling evidence that activating PPARα initiates a transcriptional program that enhances chondrocyte homeostasis.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
- Interpretationown data
FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and osteoarthritis.
“These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA.”
Quote in the paperSubstantial claim- Rests on an assumption: The association between fibrate treatment and improved osteoarthritis clinical conditions in the retrospective Osteoarthritis Initiative cohort is not confounded.
- Rests on an assumption: PPARα expression in blood is a valid proxy for PPARα expression in cartilage and for osteoarthritis status.
- Premisecitation
Cellular senescence and autophagy are potential therapeutic targets for age-related diseases.
“Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases [27].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Zhang Z. Yao Z. Zhao S. Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis Cell Death Dis. 8 6 2017 e2886 28617435 PMC5520911 source
Not checked in the free run.
- Premisecitation
Intra-articular injection of senescent cells in mice results in osteoarthritis-like pathology.
“intra-articular injection of senescent cells in mice results in OA-like pathology [13]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Xu M. Bradley E.W. Weivoda M.M. Transplanted senescent cells induce an osteoarthritis-like condition in mice J. Gerontol. Series A 72 6 2017 780 785 PMC5861939 27516624
Not checked in the free run.
- Premisecitation
Senescence-associated secretory phenotype factors released from chondrocytes are major mediators contributing to the development and progression of osteoarthritis.
“Senescence-associated secretory phenotype (SASP) factors released from chondrocytes, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, have been identified as major mediators contributing to the development and progression of OA [11,12].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11] Benderdour M. Martel-Pelletier J. Pelletier J.P. Kapoor M. Zunzunegui M.V. Fahmi H. Cellular aging, senescence and autophagy processes in osteoarthritis Curr Aging Sci 8 2 2015 147 157 26212056 source
Not checked in the free run.
- cites [12] Diekman B.O. Sessions G.A. Collins J.A. Expression of p16(INK)(4a) is a biomarker of chondrocyte aging but does not cause osteoarthritis Aging Cell 17 4 Aug 2018 e12771 PMC6052464 29744983 source
Not checked in the free run.
- Interpretationown data
PPARα agonists are senolytic in human chondrocytes.
“The PPARα agonists showed senolytic activity in human chondrocytes by reducing both the number of senescent cells and total number of cells.”
Quote in the paperSubstantial claim - Interpretationown data
FN protected against cartilage degradation in response to IL-1β treatment.
“Treatment with FN reduced proteoglycan loss in cartilage explants and protected against cartilage degradation in response to IL-1β treatment (Fig. 7a).”
Quote in the paperSubstantial claim - Interpretationown data
Genetic deletion of PPARα promoted senescence and SASP/inflammation.
“Remarkably, genetic deletion of PPARα promoted senescence and SASP/inflammation by increasing p21 and NF-κB/RELA expression levels respectively as well as increased LC3 and reduced FOXO1 expression (Fig. 7e-i).”
Quote in the paperSubstantial claim - Interpretationown data
The senolytic activity of FN in human chondrocytes is associated with selective induction of apoptosis.
“These results suggest that the senolytic activity of FN in human chondrocytes is associated with selective induction of apoptosis.”
Quote in the paperSubstantial claim - Interpretationown data
Activating lipid metabolism has a potential senotherapeutic effect in multiple senescent cell types.
“indicating the potential senotherapeutic effect of activating lipid metabolism in multiple senescent cell types”
Quote in the paperSubstantial claim - Interpretationreasoning
The regulation of senescence and autophagy markers in chondrocyte cultures by FN is likely conferred through the deletion of senescent chondrocytes.
“This regulation of senescence and autophagy markers in the chondrocyte cultures is likely conferred through the deletion of senescent chondrocytes.”
Quote in the paperSubstantial claim - Interpretationown data
PPARα agonists selectively eliminated senescent cells by increasing apoptosis following IL-6-mediated induction of senescence.
“Quantification of apoptosis demonstrated that PPARα agonists (10 and 50 μM) selectively eliminated senescenct cells by increasing apoptosis following IL-6-mediated induction of senescence (Fig. 5b).”
Quote in the paperSubstantial claim - Interpretationreasoning
Paracrine exposure of chondrocytes to IL-6 likely resembles some of the early ageing and cartilage degeneration signalling events considered key in OA development.
“Paracrine exposure of chondrocytes to IL-6 likely resembles some of the early ageing and cartilage degeneration signalling events which were considered key in OA development.”
Quote in the paperSubstantial claim - Interpretationown data
PPARα is important in maintenance of chondrocyte homeostasis.
“These results highlight the importance of PPARα in maintenance of chondrocyte homeostasis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Downregulation of the proliferation pathway may contribute to the senolytic activity of PPARα ligands.
“Downregulation of this proliferation pathway may contribute to the senolytic activity of PPARα ligands”
Quote in the paperNot a substantial claim - Premisecitation
PPARα regulates peroxisomal and mitochondrial fatty acid β-oxidation.
“Since PPARα regulates peroxisomal and mitochondrial fatty acid β-oxidation [59]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] Mascaro C. Acosta E. Ortiz J.A. Marrero P.F. Hegardt F.G. Haro D. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor J. Biol. Chem. 273 15 1998 8560 8563 9535828 source
Not checked in the free run.
- Interpretationown data
PPARα activation is a dual senolytic / autophagy enhancing strategy, identified using a human chondrocyte cell-based phenotypic screening assay.
“Here, we have identified PPARα activation as a dual senolytic / autophagy enhancing strategy by using a human chondrocyte cell-based phenotypic screening assay.”
Quote in the paperSubstantial claim - Interpretationown data
A complex interplay between elevated senescence and decreased autophagy can promote cartilage disease.
“This observation reflects a complex interplay between elevated senescence and decreased autophagy that can promote cartilage disease.”
Quote in the paperSubstantial claim - Premisecitation
PPARγ has a protective role in articular cartilage.
“it has been demonstrated that PPARγ has a protective role in articular cartilage.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [56] Vasheghani F. Monemdjou R. Fahmi H. Adult cartilage-specific peroxisome proliferator-activated receptor gamma knockout mice exhibit the spontaneous osteoarthritis phenotype Am. J. Pathol. 182 4 2013 1099 1106 23375622 source
Not checked in the free run.
- cites [57] Vasheghani F. Zhang Y. Li Y.H. PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage Ann. Rheum. Dis. 74 3 2015 569 578 25573665 PMC4345902 source
Not checked in the free run.
- Interpretationown data
Fenofibrate treatment indicates a partial reversion of the chondrocyte age-related phenotype.
“Here, we have demonstrated that the PPARα agonist fenofibrate (FN) significantly reduced chondrocyte senescence and induced autophagic flux significantly, indicating a partial reversion of the chondrocyte age-related phenotype.”
Quote in the paperSubstantial claim - Interpretationown data
These clinical findings support the hypothesis that fibrates may improve joint function in human OA patients.
“These clinical findings support the hypothesis that fibrates may improve joint function in human OA patients”
Quote in the paperSubstantial claim - Premisecitation
Pain and functional limitation in knee OA are closely related.
“pain and functional limitation in knee OA are closely related [64].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] McAlindon T.E. Cooper C. Kirwan J.R. Dieppe P.A. Determinants of disability in osteoarthritis of the knee Ann. Rheum. Dis. 52 4 1993 258 262 8484690 PMC1005622 source
Not checked in the free run.
- Interpretationcitation
The reduction in disability found in the present study may be explained by the emerging anxiolytic effects of PPARα agonism.
“one of the explanations of the reduction in disability found in the present study may be the observed emerging anxiolytic effects of PPARα agonism [66].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Nisbett K.E. Pinna G. Emerging therapeutic role of PPAR-alpha in cognition and emotions Front. Pharmacol. 9 2018 998 30356872 PMC6190882 source
Not checked in the free run.
- Interpretationown data
PPARα downregulation in spontaneous ageing-related and surgically induced OA mouse models, as well as in blood and cartilage from patients with knee OA, indicates an intrinsic OA-related PPARα defect.
“PPARα was found to be downregulated in spontaneous ageing-related and surgically induced OA mouse models, as well as in blood and cartilage from patients with knee OA, indicating an intrinsic OA-related PPARα defect.”
Quote in the paperSubstantial claim - Interpretationreasoning
These results are consistent with a positive remodelling of cartilage metabolism that protects against ageing and disease signals.
“These results are consistent with a positive remodelling of cartilage metabolism that protects against ageing and disease signals.”
Quote in the paperSubstantial claim - Interpretationreasoning
Regulation of lipid metabolism by PPARα can be considered as a potential therapeutic target for OA.
“In conclusion, regulation of lipid metabolism by PPARα can be considered as a potential therapeutic target for OA.”
Quote in the paperSubstantial claim - Interpretationreasoning
PPARα agonists regulate mitochondrial fatty acid β-oxidation in human chondrocytes.
“suggesting that these ligands regulate mitochondrial fatty acid β-oxidation in human chondrocytes.”
Quote in the paperSubstantial claim - Premisecitation
In an open label study on patients with erosive hand OA, FN use for 12 weeks was associated with significant improvements in the Cochin hand functional disability scale.
“These findings are in line with an open label study performed on patients with erosive hand OA where FN use for 12 weeks was associated with significant improvements in the Cochin hand functional disability scale [61].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [61] Shirinsky I.V. Shirinsky V.S. Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study Rheumatol. Int. 34 5 2014 613 616 23620259 source
Not checked in the free run.
- May combine two claims. 20
- Classified as probably not a substantial claim. 21
May combine two claims.
Findingown dataFenofibrate and other ligands prevent cartilage degradation and positively modulate senescence and autophagy in chondrocytes and cartilage.
“Moreover, FN and other ligands were able to prevent cartilage degradation and to positively modulate key molecular mechanisms such as senescence and autophagy in chondrocytes and cartilage.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
May combine two claims.
Findingown dataFenofibrate reduces senescence and inflammation in both ageing human and osteoarthritis chondrocytes.
“FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
- Rests on an assumption: The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
May combine two claims.
FindingcitationSenescence was induced by treatment with SASP factor IL-6, increasing SA-β-Gal activity and p21 expression, while decreasing autophagic flux and inducing the mTOR signalling pathway.
“Senescence was induced by treatment with SASP factor IL-6 [53], increasing SA-β-Gal activity and p21 expression, while decreasing autophagic flux and inducing the mTOR signalling pathway.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Kojima H. Inoue T. Kunimoto H. Nakajima K. IL-6-STAT3 signaling and premature senescence Jak-stat 2 4 2013 e25763 PMC3876432 24416650 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataA number of ion channels and pumps disruptors were identified in the screening assay.
“A number of ion channels and pumps disruptors were identified.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationArticular cartilage of patients with osteoarthritis shows features of senescence, including increased nitric oxide and pro-inflammatory cytokines, p16, activated DNA damage response, ROS secretion and SA-β-Gal activity.
“Articular cartilage of patients with OA shows features of senescence, including increased expression of nitric oxide, pro-inflammatory cytokines, particularly IL-1β [8]; p16 [9]; activated DNA damage response; ROS secretion and SA-β-Gal activity [10].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Abramson S.B. Attur M. Amin A.R. Clancy R. Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis Curr. Rheumatol. Rep. 3 6 2001 535 541 11709117 source
Not checked in the free run.
- cites [9] Zhou H.W. Lou S.Q. Zhang K. Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro Rheumatology (Oxford) 43 5 2004 555 568 15026580 source
Not checked in the free run.
- cites [10] Price J.S. Waters J.G. Darrah C. The role of chondrocyte senescence in osteoarthritis Aging Cell 1 1 2002 57 65 12882354 source
Not checked in the free run.
May combine two claims.
PremisecitationNeither preventive measures nor disease-modifying treatments for osteoarthritis are yet available.
“for which disease-modifying treatments are not available”
- Also stated in: § Introduction · plain
“neither preventive measures nor disease-modifying treatments are yet available [2]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Lotz M.K. Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA Nat. Rev. Rheumatol. 7 10 2011 579 587 21808292 PMC3192496 source
Not checked in the free run.
- Also stated in: § Introduction · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe dasatinib and quercetin combination is efficacious in several models of age-related disease, extends healthspan and lifespan in mice, and protects from idiopathic fibrosis in a first-in-human trial.
“the efficacy of dasatinib and quercetin combination in several models of age-related disease, which results in an extension of healthspan and lifespan in mice [6], as well as protects from idiopathic fibrosis in a first-in-human trial [16].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Xu M. Pirtskhalava T. Farr J.N. Senolytics improve physical function and increase lifespan in old age Nat. Med. 24 8 2018 1246 1256 29988130 PMC6082705 source
Not checked in the free run.
- cites [16] Justice J.N. Nambiar A.M. Tchkonia T. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study EBioMedicine 40 2019 554 563 30616998 PMC6412088 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationActivating FoxO transcription factors protects against osteoarthritis-associated cartilage damage.
“Activating FoxO transcription factors protect against OA-associated cartilage damage [26].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Matsuzaki T. Alvarez-Garcia O. Mokuda S. FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis Sci. Transl. Med. 10 428 2018 PMC6204214 29444976 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPhysical activity intervention in rats ameliorates the deleterious effects of chondrocyte senescence and ageing, indicating that cartilage degeneration responds to environmental signals.
“Physical activity intervention in rats ameliorates the deleterious effects of chondrocyte senescence and ageing [15], indicating that cartilage degeneration responds to environmental signals.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Musumeci G. Castrogiovanni P. Trovato F.M. Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression Scand. J. Med. Sci. Sports 25 2 2015 e222 e230 25039883 source
Not checked in the free run.
May combine two claims.
Interpretationown dataFN regulates homeostasis in human chondrocytes as both a senolytic and autophagy modulating compound.
“Taken together, these results demonstrate that FN regulates homeostasis in human chondrocytes as both a senolytic and autophagy modulating compound (Fig. 6d).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPPARα is a therapeutic target for lipid metabolism dysfunction.
“Peroxisome proliferator-activated receptor alpha (PPARα), a therapeutic target for lipid metabolism dysfunction [32]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Hulsmans M. Geeraert B. Arnould T. Tsatsanis C. Holvoet P. PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression PLoS One 8 4 2013 e62253 PMC3631170 23620818 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRapamycin and chloroquine showed the expected effects as positive and negative controls for autophagic flux.
“Rapamycin and chloroquine (CQ) showed the expected effects as positive and negative controls for autophagic flux (Fig. 6a).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCartilage-specific PPARγ deficient mice showed increased apoptosis, increased production of inflammatory and catabolic factors, decreased expression of anabolic factors, and accelerated OA.
“Cartilage-specific PPARγ deficient mice showed increased apoptosis as well as production of inflammatory and catabolic factors, and a decreased expression of anabolic factors, overall resulting in accelerated OA [56,57].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [56] Vasheghani F. Monemdjou R. Fahmi H. Adult cartilage-specific peroxisome proliferator-activated receptor gamma knockout mice exhibit the spontaneous osteoarthritis phenotype Am. J. Pathol. 182 4 2013 1099 1106 23375622 source
Not checked in the free run.
- cites [57] Vasheghani F. Zhang Y. Li Y.H. PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage Ann. Rheum. Dis. 74 3 2015 569 578 25573665 PMC4345902 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenThe OAI cohort consists of a progression subcohort (n=1390), an incidence subcohort (n=3284), and a reference control subcohort (n=122).
“The OAI cohort consists of a progression subcohort (patients with symptomatic tibiofemoral knee OA, n = 1390), an incidence subcohort (subjects with increased risk of OA, n = 3284) and a reference control subcohort (n = 122).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe data sets generally followed a normal distribution.
“In general, the data sets followed a normal distribution.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Premiseown dataThe OAI progression subcohort included patients aged 45-79 with symptomatic tibiofemoral knee OA, and the incidence subcohort included subjects aged 45-79 with established or putative risk factors for incident knee OA.
“The main inclusion criteria were the following: age between 45 and 79 years for both subcohorts, symptomatic tibiofemoral knee OA for the progression subcohort, and the presence of established or putative risk factors for incident knee OA for the incidence subcohort.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataGenetic matching was used to match fibrate users with non-users.
“The genetic matching method was used to match fibrate users with non-users.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe prespecified sample size for the OAI study was 5000 participants (4000 in the incidence subcohort, 800 in the progression subcohort).
“The prespecified sample size was 5000 participants (4000 in the incidence subcohort, 800 in the progression subcohort).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataLC3 might act as a regulator of lipid signals influencing homeostasis.
“which might act as a regulator of lipid signals influencing homeostasis.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataAfter genetic matching, all standardized differences of means decreased to <0.05, indicating the matched groups had <5% of standard deviation difference in corresponding variables, and covariates were considered well balanced between groups.
“After matching, all standardized differences of means decreased to <0.05, indicating that the matched groups had <5% of standard deviation difference in the corresponding variables. Therefore, it was considered that covariates were well balanced between groups (Supplementary Table 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPPARα regulates fatty acid β-oxidation and is involved in regulation of energy homeostasis.
“PPARα regulates fatty acid (FA) β-oxidation and is involved in regulation of energy homeostasis [52].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Tyagi S. Gupta P. Saini A.S. Kaushal C. Sharma S. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases J Adv Pharm Technol Res 2 4 2011 236 240 22247890 PMC3255347 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductcitationAfter matching, differences between the two groups were compared by standardized differences, with ≥ 0.1 defined as meaningful disbalance.
“After all matches were done, differences between the two groups were compared by standardized differences, ≥ 0.1 was defined as meaningful disbalance [45].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] Austin P.C. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples Stat. Med. 28 25 2009 3083 3107 19757444 PMC3472075 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThese data are consistent with FN treatment inducing the selective elimination of senescent cells and favorably modulating inflammatory and metabolic responses involved in OA pathogenesis.
“These data are consistent with FN treatment inducing the selective elimination of senescent cells and favorably modulating inflammatory and metabolic responses involved in OA pathogenesis.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationCPT1A is a target gene of PPARα.
“a target gene of PPARα [60]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Xiao Y. Wang J. Yan W. Zhou K. Cao Y. Cai W. p38alpha MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure Cell Death Dis. 8 10 2017 e3110 29022907 PMC5682685 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataThe matching adjusted for demographic characteristics, body mass index, prior knee surgery, baseline outcome measures, and PASE.
“The following potential confounding variables were used for the matching: demographic characteristics, body mass index, prior knee surgery, baseline outcome measures, and PASE.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThis study was approved by institutional review board committees from each recruitment centre, and all participants provided written informed consent.
“This study was approved by institutional review board committees from each recruitment centre. Before entering the study, all participants provided written informed consent.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIL-6-induced inflammation and senescence is accompanied by decreased autophagy in chondrocytes, suggesting a homeostatic imbalance.
“These results also suggest an interesting homeostatic imbalance, whereby IL-6-induced inflammation and senescence is accompanied by decreased autophagy in chondrocytes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGEE allows for not using imputation methods for missing data because participants with missing data are not excluded from the analysis.
“GEE allows for not using imputation methods for the missing data, because the participants with missing data are not excluded from the analysis [46].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Twisk J. de Vente W. Attrition in longitudinal studies. How to deal with missing data J. Clin. Epidemiol. 55 4 2002 329 337 11927199 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPPARα is an established modulator of lipid metabolism.
“the PPARα nuclear receptor was of prime interest because is an established modulator of lipid metabolism”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [54] Narala V.R. Adapala R.K. Suresh M.V. Brock T.G. Peters-Golden M. Reddy R.C. Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist J. Biol. Chem. 285 29 2010 22067 22074 20400503 PMC2903376 source
Not checked in the free run.
- cites [55] Clockaerts S. Bastiaansen-Jenniskens Y.M. Feijt C. Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage Osteoarthr. Cartil. 19 7 2011 895 902 21458577 source
Not checked in the free run.
May combine two claims.
InterpretationcitationThe prevalent user design used in that study may be associated with bias and may account for the non-detection of fibrate effect on pain.
“used a prevalent user design (i.e. included participants who used fibrates at baseline) [62] that may be associated with bias [63] and may account for the non-detection of fibrate effect on pain.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [62] Driban J.B. Lo G.H. Eaton C.B. Exploratory analysis of osteoarthritis progression among medication users: data from the osteoarthritis initiative Ther Adv Musculoskelet Dis 8 6 2016 207 219 28321269 PMC5322858 source
Not checked in the free run.
- cites [63] Ray W.A. Evaluating medication effects outside of clinical trials: new-user designs Am. J. Epidemiol. 158 9 2003 915 920 14585769 source
Not checked in the free run.
May combine two claims.
PremisecitationIn an exploratory study through the OAI database, neither reduced radiographic progression nor reduction in worsening of pain in participants taking fibrates were detected.
“In another exploratory study carried out through the OAI database, neither reduced radiographic progression nor reduction in worsening of pain in participants taking fibrates were detected.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] Driban J.B. Lo G.H. Eaton C.B. Exploratory analysis of osteoarthritis progression among medication users: data from the osteoarthritis initiative Ther Adv Musculoskelet Dis 8 6 2016 207 219 28321269 PMC5322858 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThe lack of association between fibrate use and pain reduction may be due to absence of analgesic properties of PPARα agonists or may be due to reduced statistical power caused by small sample size.
“the lack of association between fibrate use and pain reduction may be due to absence of analgesic properties of PPARα agonists or may be due to reduced statistical power caused by small sample size.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAnxiety is one of the determinants of functioning in knee OA.
“As anxiety has been shown to be one of the determinants of functioning in knee OA [65]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Creamer P. Lethbridge-Cejku M. Hochberg M.C. Factors associated with functional impairment in symptomatic knee osteoarthritis Rheumatology (Oxford) 39 5 2000 490 496 10852978 source
Not checked in the free run.
The paper relies on this without support.
IL-6 treatment induces senescence and suppresses autophagy in human chondrocytes.
“Human chondrocytes with IL-6 induced senescence and autophagy suppression”
“Senescence was induced in the T/C28a2 human chondrocyte cell line by IL-6 treatment”
The paper relies on this without support.
The T/C28a2 immortalized human chondrocyte cell line is a valid model of primary human chondrocyte senescence and osteoarthritis.
“The immortalized human juvenile chondrocyte cell line T/C28a2 [33], was cultured in DMEM supplemented with 10% FCS and 100 IU/ml Penicillin / 100 μg/ml Streptomycin at 37 °C and 5% CO2.”
The paper relies on this without support.
The association between fibrate treatment and improved osteoarthritis clinical conditions in the retrospective Osteoarthritis Initiative cohort is not confounded.
“in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort.”
The paper relies on this without support.
PPARα expression in blood is a valid proxy for PPARα expression in cartilage and for osteoarthritis status.
“PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients.”
The authors state this as an assumption.
The outcome parameters develop linearly over time.
“assuming linear development over time”
The authors state this as an assumption.
The correlation structure selected for the GEE models is correct.
“Although selection of proper correlation structure is the assumption in GEE models”
The paper relies on this without support.
Disease-modifying therapeutic agents to prevent or stop progression of OA are an urgent clinical need.
“Disease-modifying therapeutic agents to prevent or stop progression of OA are an urgent clinical need.”
The paper relies on this without support.
PPARα auto-regulates its own expression.
“PPARα also appears to auto-regulate its own expression.”
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?
Fenofibrate can induce selective elimination of senescence cells through upregulating PPARα expression.
“In addition, another Senolytic called Fenofibrate can induce selective elimination of senescence cells through upregulating PPARα expression.347”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [347]
The Results section reports that fenofibrate selectively eliminates senescent chondrocytes by inducing apoptosis, and a separate Results section reports increased PPARα gene and protein expression after fenofibrate treatment (pages not provided). The paper describes fenofibrate as a PPARα agonist, but does not establish that increased PPARα expression is the mechanism of elimination; it links elimination to apoptosis. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Surgical OA mouse sample size differs between methods and figure
MajorThe histological methods give n = 3 for the sham and surgical OA groups, while the corresponding Fig. 9 quantification states four mice per group.
“(sham surgery and 10 weeks after surgery; n = 3)”
“d, Quantification of PPARα-positive cells. Values are the mean ± SEM of 4 mice per group.”
GW7647 and CP775146 figure references are reversed
MinorThe results attribute the GW7647 finding to Fig. 4b and the CP775146 finding to Fig. 4c, whereas the figure legend identifies 4b as CP and 4c as GW.
“GW7647 was toxic at 50 μM (Fig. 4b) and CP775146 was senolytic only at 12.5 μM (Fig. 4c).”
“b. T/C28a2 human chondrocytes were treated with IL-6 (20 ng/ml) in combination with CP (1,582 – 50 μM)”
Positive coefficients are described as yearly decreases
MinorThe paper defines the user-by-time β-coefficient as a yearly change, but reports positive coefficients of 1.15 and 1.6 as decreases in WOMAC scores. A decrease would require negative coefficients under that definition.
“an average yearly decrease in WOMAC function grade by 1.15 and WOMAC total score by 1.6, as reflected by β-coefficients of 1.15 and 1.6, respectively”
“A β-coefficient for this interaction term indicates yearly change in the outcome parameter assuming linear development over time.”
Two-month-old mice appear in the figure but not the methods age groups
MinorThe methods list 6, 12, 18 and 30 months for the spontaneous ageing-related OA mouse model, but Fig. 9 includes a 2-month-old group and uses it as the comparison group.
“Knee joints from 6, 12, 18 and 30-month-old C57BL/6 J mice with spontaneous ageing-related OA (n = 3 per time point)”
“Representative images of knee joints from 2, 6, 12, 18 and 30-month-old mice stained with Safranin O-Fast Green and PPARα.”
The citation lists haven’t been fetched yet
References 66 · Cited by 155
- Authors
- Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., Shirinsky, I., Lotz, M., Robbins, P. D., Domínguez, E., & Caramés, B.
- Affiliations
- Complexo Hospitalario Universitario A Coruña (ES)
- Institut Interdisciplinaire de Neuroscience (FR)
- Research Institute of Fundamental and Clinical Immunology (RU)
- University of Minnesota (US)
- Universidade de Santiago de Compostela (ES)
- Corresponding author
- Domínguez, Eduardo
- Caramés, Beatriz
- ORCID
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 45
- Pages
- 588-605
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC6642320
- OpenAlex
- W2954146550
- Cited by
- 155
- References
- 66
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 24 · 2023: 15 · 2022: 26 · 2021: 22 · 2020: 23 · 2019: 4
- FWCI
- 14.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion, cc-by-nc-nd)
- RUC (Universidade Da Coruña) (submittedVersion, cc-by-nc-nd)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, cc-by-nc-nd)
- Funders
- Instituto de Salud Carlos III
- Ministerio de Ciencia, Innovación y Universidades
- Fondo Europeo de Desarrollo Regional
- Una manera de hacer Europa (PI14/01324, PI17/02059)
- Ministerio de Economía y Competitividad
- National Institutes of Health (P01 AG043376, U19 AG056278)
- Xunta de Galicia
- Miguel Servet Type II Program (CPII16/00045-A)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- osteoarthritis, senolytics, autophagy, chondrocyte senescence, PPARα agonist, fenofibrate, fibrates, cartilage degeneration, aging, drug repurposing, Osteoarthritis Initiative, articular cartilage, inflammation, apoptosis, lipid metabolism, senotherapeutics
- MeSH terms
- Aging, Animals, Autophagy, Cartilage Diseases, Cartilage, Articular, Cells, Cultured, Humans, Osteoarthritis, Fenofibrate, Interleukin-6, Cellular Senescence, Apoptosis, Chondrocytes, PPAR alpha, Lipid Metabolism, Mice
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
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