Background:Obesity increases knee osteoarthritis(OA) risk through metabolic,inflammatory,and biomechanical factors,but how these systemic and local mediators interact to drive OA pathology is not well understood.We te...Background:Obesity increases knee osteoarthritis(OA) risk through metabolic,inflammatory,and biomechanical factors,but how these systemic and local mediators interact to drive OA pathology is not well understood.We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice.We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups.Methods:Male C57 BL/6 J mice were fed a defined control(10% kcal fat) or high fat(HF)(60% kcal fat) diet from 6 to 37 weeks of age.At 25 weeks,one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study.Histology,micro computed tomography,and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology.These local variables were then compared to systemic metabolic(body mass,body fat,and glucose tolerance),inflammatory(serum adipokines and inflammatory mediators),and functional(mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis.Diet and exercise effects were evaluated by two-way analysis of variance.Results:An HF diet increased the infrapatellar fat pad size and posterior joint osteophytes,and wheel running primarily altered the subchondral cortical and trabecular bone.Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups.However,the coefficient of variation was≥25% for many outcomes,and some mice in both diet groups developed moderate OA(>33% maximum score).This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes.In wheel-running cohorts,an HF diet reduced the network size compared to the control diet group despite similar running distances,suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors.Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA.Conclusion:Despite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations,diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA.These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease.展开更多
Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Und...Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes.CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting;however,CC can impair other organs such as the liver,heart,brain,and bone as well.A considerable amount of CC research focuses on changes that occur within the muscle,but cancer-related impairments in other organ systems are understudied.Furthermore,metabolic changes in organ systems other than muscle may contribute to CC.Therefore,the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective.Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC.As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from preclinical models.展开更多
Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tum...Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tumor are likely causes for poor outcomes.We previously reported that BMI1,a stem-cell factor is instrumental in regulating chemoresistance.2,3 However,to advance anti-BMI1 therapy from the bench to the bedside,efficacy needs to be tested in patient-derived chemoresistant HGSOC models,which is lacking.展开更多
基金supported by the National Institutes of Health(P20RR018758,P20GM103441,P30GM114731,R03AR066828,and R01AG049058 to Dr.Griffin)the Arthritis Foundation(Arthritis Investigator Award to Dr.Griffin)。
文摘Background:Obesity increases knee osteoarthritis(OA) risk through metabolic,inflammatory,and biomechanical factors,but how these systemic and local mediators interact to drive OA pathology is not well understood.We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice.We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups.Methods:Male C57 BL/6 J mice were fed a defined control(10% kcal fat) or high fat(HF)(60% kcal fat) diet from 6 to 37 weeks of age.At 25 weeks,one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study.Histology,micro computed tomography,and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology.These local variables were then compared to systemic metabolic(body mass,body fat,and glucose tolerance),inflammatory(serum adipokines and inflammatory mediators),and functional(mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis.Diet and exercise effects were evaluated by two-way analysis of variance.Results:An HF diet increased the infrapatellar fat pad size and posterior joint osteophytes,and wheel running primarily altered the subchondral cortical and trabecular bone.Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups.However,the coefficient of variation was≥25% for many outcomes,and some mice in both diet groups developed moderate OA(>33% maximum score).This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes.In wheel-running cohorts,an HF diet reduced the network size compared to the control diet group despite similar running distances,suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors.Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA.Conclusion:Despite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations,diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA.These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease.
基金Authors would like to thank the dedicated faculty,staff and students at both the Exercise Science Research Center at the University of Arkansas and the Aging and Metabolism Research Program at the Oklahoma Medical Research Foundation for their consistent support of this research.Work presented here was funded by National Institutes of Health under Award Number R15AR069913 and R01AR075794 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of General Medical SciencesAuthor Jacob L.Brown is supported by National Institute of Aging at the National Institutes of Health 5T32AG052363-02.
文摘Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes.CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting;however,CC can impair other organs such as the liver,heart,brain,and bone as well.A considerable amount of CC research focuses on changes that occur within the muscle,but cancer-related impairments in other organ systems are understudied.Furthermore,metabolic changes in organ systems other than muscle may contribute to CC.Therefore,the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective.Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC.As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from preclinical models.
基金This study was supported by research awards from the US Department of Defense to RB(No.W81XWH1810073,and W81XWH1810054)Histology and immunohistochemistry service was provided by the Stephenson Cancer Tissue Pathology research core supported by the NIGMS Grant P20GM103639 and NCI Grant P30CA225520 of the NIH.
文摘Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tumor are likely causes for poor outcomes.We previously reported that BMI1,a stem-cell factor is instrumental in regulating chemoresistance.2,3 However,to advance anti-BMI1 therapy from the bench to the bedside,efficacy needs to be tested in patient-derived chemoresistant HGSOC models,which is lacking.
