Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility,...Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their role was not defined. We further show that bone particles and IL-1β can promote senescent and apoptotic changes in primary chondrocytes due to oxidative stress from various cellular sources such as the mitochondria. Finally, we provide evidence that inflammation, oxidative stress and senescence converge upon IκB-ζ, the principal mediator downstream of NF-κB, which regulates expression of RANKL, inflammatory, catabolic,and SASP genes. Overall, this work highlights the capacity and mechanisms by which inflammatory cues, primarily joint degradation products, i.e., bone matrix particles in concert with IL-1β in the joint microenvironment, program chondrocytes into an “inflammatory phenotype” which inflects local tissue damage.展开更多
Fragile X Messenger Ribonucleoprotein 1(FMR1)gene mutations lead to fragile X syndrome,cognitive disorders,and,in some individuals,scoliosis and craniofacial abnormalities.Four-month-old(mo)male mice with deletion of ...Fragile X Messenger Ribonucleoprotein 1(FMR1)gene mutations lead to fragile X syndrome,cognitive disorders,and,in some individuals,scoliosis and craniofacial abnormalities.Four-month-old(mo)male mice with deletion of the FMR1 gene exhibit a mild increase in cortical and cancellous femoral bone mass.However,consequences of absence of FMR1 in bone of young/aged male/female mice and the cellular basis of the skeletal phenotype remain unknown.We found that absence of FMR1 results in improved bone properties with higher bone mineral density in both sexes and in 2-and 9-mo mice.The cancellous bone mass is higher only in females,whereas,cortical bone mass is higher in 2-and 9-mo males,but higher in 2-and lower in 9-mo female FMR1-knockout mice.Furthermore,male bones show higher biomechanical properties at 2mo,and females at both ages.Absence of FMR1 increases osteoblast/mineralization/bone formation and osteocyte dendricity/gene expression in vivo/ex vivo/in vitro,without affecting osteoclasts in vivo/ex vivo.Thus,FMR1 is a novel osteoblast/osteocyte differentiation inhibitor,and its absence leads to age-,site-and sex-dependent higher bone mass/strength.展开更多
Acoustic signals play a crucial role in transmitting information and maintaining social stability in gregarious animals,especially in echolocating bats,which rely primarily on biological sonar for navigating in ...Acoustic signals play a crucial role in transmitting information and maintaining social stability in gregarious animals,especially in echolocating bats,which rely primarily on biological sonar for navigating in the dark.In the context of foraging without relying on tactile,visual or olfactory cues,acoustic signals convey information not only on food but also on ownership and defense of resources.However,studies on such information remain fragmentary.In the present study,we aim to document the social vocal repertoire of Myotis macrodactylus at natural foraging sites.Multiple acoustic analyses and spectrographic classification revealed a rich foraging vocal repertoire comprising 6 simple syllables and 2 composites.Discriminant function analyses associated with a subset-validation procedure provided an optimal method to spectrographically classify all recorded sounds into different syllable types.Multidimensional scaling of median values of multiple parameters further confirmed notable differences among these syllables in a 3-D space.In addition,Euclidean distance analysis showed that there were some spectral similarities between specific social vocal syllables and feeding buzzes,which implied a potential jamming role.Altogether,the data indicate that bats at foraging sites under natural conditions used variant social vocalizations with different functions in addition to echolocation calls,providing supporting evidence for further work on the function and vocal mechanisms of acoustic communication in mammals.展开更多
Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury(TBI).However,the efficacy of exercise is limited during the acute period o...Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury(TBI).However,the efficacy of exercise is limited during the acute period of TBI because of metabolic dysfunction,and this may further compromise neuronal function.Here we discuss the possibility to normalize brain metabolism during the early post-injury convalescence period to support functional plasticity and prevent long-term functional deficits.Although BDNF possesses the unique ability to support molecular events involved with the transmission of information across nerve cells through activation of its TrkB receptor,the poor pharmacokinetic profile of BDNF has limited its therapeutic applicability.The flavonoid derivative,7,8-dihydroxyflavone(7,8-DHF),signals through the same TrkB receptors and results in the activation of BDNF signaling pathways.We discuss how the pharmacokinetic limitations of BDNF may be avoided by the use of 7,8-DHF,which makes it a promising pharmacological agent for supporting activity-based rehabilitation during the acute post-injury period after TBI.In turn,docosahexaenoic acid(C22:6n-3;DHA)is abundant in the phospholipid composition of plasma membranes in the brain and its action is important for brain development and plasticity.DHA is a major modulator of synaptic membrane fluidity and function,which is fundamental for supporting cell signaling and synaptic plasticity.Exercise influences DHA function by normalizing DHA content in the brain,such that the collaborative action of exercise and DHA can be instrumental to boost BDNF function with strong therapeutic potential for reducing the deleterious effects of TBI on synaptic plasticity and cognition.展开更多
基金supported by NIH/NIAMS R01-AR049192, R01-AR054326 (to YA)Biomedical grant from Shriners Hospital for Children (YA), P30 AR074992 NIH Core Center for Musculoskeletal Biology and Medicine (to YA)NIH/NIAMS R01AR064755 and R01-AR068972 (to GM)
文摘Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their role was not defined. We further show that bone particles and IL-1β can promote senescent and apoptotic changes in primary chondrocytes due to oxidative stress from various cellular sources such as the mitochondria. Finally, we provide evidence that inflammation, oxidative stress and senescence converge upon IκB-ζ, the principal mediator downstream of NF-κB, which regulates expression of RANKL, inflammatory, catabolic,and SASP genes. Overall, this work highlights the capacity and mechanisms by which inflammatory cues, primarily joint degradation products, i.e., bone matrix particles in concert with IL-1β in the joint microenvironment, program chondrocytes into an “inflammatory phenotype” which inflects local tissue damage.
基金supported by the National Institutes of Health R01-AR053643Veterans Research Administration Merit Award I01BX00515+7 种基金a Research Support Funds Grant(RSFG),Indiana University Purdue University Indianapolis-Office of the Vice Chancellor for Research,Indianapolis to LIP.supported by ASBMR Fund for Research and Education Research and Collaborative Grant Programsupported by the National Institutes of Health R01AG067997 to CJHsupported by the IUPUI Diversity Scholars Research Program(DSRP)Diversity Summer Undergraduate Research Opportunity Program(DS-UROP)Indiana CTSI Student Summer Research ProgramIUPUI work study programsupported by the Life Health Science Internship(LHSI)。
文摘Fragile X Messenger Ribonucleoprotein 1(FMR1)gene mutations lead to fragile X syndrome,cognitive disorders,and,in some individuals,scoliosis and craniofacial abnormalities.Four-month-old(mo)male mice with deletion of the FMR1 gene exhibit a mild increase in cortical and cancellous femoral bone mass.However,consequences of absence of FMR1 in bone of young/aged male/female mice and the cellular basis of the skeletal phenotype remain unknown.We found that absence of FMR1 results in improved bone properties with higher bone mineral density in both sexes and in 2-and 9-mo mice.The cancellous bone mass is higher only in females,whereas,cortical bone mass is higher in 2-and 9-mo males,but higher in 2-and lower in 9-mo female FMR1-knockout mice.Furthermore,male bones show higher biomechanical properties at 2mo,and females at both ages.Absence of FMR1 increases osteoblast/mineralization/bone formation and osteocyte dendricity/gene expression in vivo/ex vivo/in vitro,without affecting osteoclasts in vivo/ex vivo.Thus,FMR1 is a novel osteoblast/osteocyte differentiation inhibitor,and its absence leads to age-,site-and sex-dependent higher bone mass/strength.
基金the National Natural Science Foundation of China(Grant Nos.31770429,31370411 and 31670390)the Fundamental Research Funds for the Central Universities(Grant No.2412016KJ045)+2 种基金the Overseas Famous Experts Project of the Ministry of Education of China(Grant No.MS2011DBSF023)the Program for Introducing Talents to Universities(Grant No.B16011)a grant for“1000 Talent Plan for High-Level Foreign Experts”from the Organization Department of the CPC Central Committee(Grant No.WQ20142200259).
文摘Acoustic signals play a crucial role in transmitting information and maintaining social stability in gregarious animals,especially in echolocating bats,which rely primarily on biological sonar for navigating in the dark.In the context of foraging without relying on tactile,visual or olfactory cues,acoustic signals convey information not only on food but also on ownership and defense of resources.However,studies on such information remain fragmentary.In the present study,we aim to document the social vocal repertoire of Myotis macrodactylus at natural foraging sites.Multiple acoustic analyses and spectrographic classification revealed a rich foraging vocal repertoire comprising 6 simple syllables and 2 composites.Discriminant function analyses associated with a subset-validation procedure provided an optimal method to spectrographically classify all recorded sounds into different syllable types.Multidimensional scaling of median values of multiple parameters further confirmed notable differences among these syllables in a 3-D space.In addition,Euclidean distance analysis showed that there were some spectral similarities between specific social vocal syllables and feeding buzzes,which implied a potential jamming role.Altogether,the data indicate that bats at foraging sites under natural conditions used variant social vocalizations with different functions in addition to echolocation calls,providing supporting evidence for further work on the function and vocal mechanisms of acoustic communication in mammals.
基金supported by the National Institutes of Health(grant numbers:NS111378,NS117148,NS050465,NS116838).
文摘Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury(TBI).However,the efficacy of exercise is limited during the acute period of TBI because of metabolic dysfunction,and this may further compromise neuronal function.Here we discuss the possibility to normalize brain metabolism during the early post-injury convalescence period to support functional plasticity and prevent long-term functional deficits.Although BDNF possesses the unique ability to support molecular events involved with the transmission of information across nerve cells through activation of its TrkB receptor,the poor pharmacokinetic profile of BDNF has limited its therapeutic applicability.The flavonoid derivative,7,8-dihydroxyflavone(7,8-DHF),signals through the same TrkB receptors and results in the activation of BDNF signaling pathways.We discuss how the pharmacokinetic limitations of BDNF may be avoided by the use of 7,8-DHF,which makes it a promising pharmacological agent for supporting activity-based rehabilitation during the acute post-injury period after TBI.In turn,docosahexaenoic acid(C22:6n-3;DHA)is abundant in the phospholipid composition of plasma membranes in the brain and its action is important for brain development and plasticity.DHA is a major modulator of synaptic membrane fluidity and function,which is fundamental for supporting cell signaling and synaptic plasticity.Exercise influences DHA function by normalizing DHA content in the brain,such that the collaborative action of exercise and DHA can be instrumental to boost BDNF function with strong therapeutic potential for reducing the deleterious effects of TBI on synaptic plasticity and cognition.
