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Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain

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Bone Research 2024年第1期12卷 107-121页

作者： Feng Gao Qimiao Hu Wenwei Chen Jilong Li Cheng Qi Yiwen Yan Cheng Qian Mei Wan James Ficke Junying Zheng xu cao Department of Orthopedic Surgery Johns Hopkins University School of MedicineBaltimoreMaryland 21205USA Department of Biomedical Engineering Johns Hopkins University School of MedicineBaltimoreMaryland 21205USA

Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment.However,it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain.In this study,we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2(PGE2)concentration in response to mechanical loading.Bone PGE2 levels are in proportion to their weight bearing.When weight bearing changes in the tail-suspension mice,the PGE2 concentrations in bones change in line with their weight bearing changes.Deletion of cyclooxygenase-2(COX2)in the osteoblast lineage cells or knockout of receptor 4(EP4)in sensory nerve blunts bone formation in response to mechanical loading.Moreover,knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation.Moreover,mechanical loading induces cAMP-response element binding protein(CREB)phosphorylation in the hypothalamic arcuate nucleus(ARC)to inhibit sympathetic tyrosine hydroxylase(TH)expression in the paraventricular nucleus(PVN)for osteogenesis.Finally,we show that elevated PGE2 is associated with ankle osteoarthritis(AOA)and pain.Together,our data demonstrate that in response to mechanical loading,skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis,while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

关键词： pain elevated PGE2

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Photo-and electro-production of narrow exotic states:From light quarks to charm and up to bottom

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Frontiers of physics 2023年第4期18卷 71-94页

作者： xu cao Institute of Modern Physics Chinese Academy of SciencesLanzhou 730000 China University of Chinese Academy of Sciences Beijing 100049China Research Center for Hadron and CSR Physics Lanzhou University and Institute of Modern Physics of CASLanzhou 730000China

Accessing a full image of the inner content of hadrons represents a central endeavour of modern particle physics,with the main scientific motivation to investigate the strong interaction binding the visible matter.On the one hand,the structure of known exotic candidates is a fundamental open issue addressed widely by scientists.On the other hand,looking for new states of exotic nature is a central component for theoretical and experimental efforts from electron-positron machine and electron accelerator with fixed target to heavy ion and electron-ion colliders.In this article we present a succinct short overview of the attempt to search for exotic narrow N∗and Z states containing light quarks only or also charm,and its connotation for bottom regions(the latter two are also known as Pc(Zc)and Pb(Zb)states,respectively in the literature).We address the effort of searching for exotic narrow N∗and Z states in light quark sector.We focus on recent progress in searching for signal of Pc and Zc states photoproduction and its implication into the Pb and Zb photoproduction and their decay properties.We also discuss future perspectives for the field in electron-ion colliders,a good place to disentangle the nature of some of these states and investigate some other enlightening topics including QCD trace anomaly and quarkonium-nucleon scattering length.

关键词： exotic states photo-and electro-production electron-ion colliders hadron

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The structural characteristics of dietary fibers from Tremella fuciformis and their hypolipidemic effects in mice

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Food Science and Human Wellness 2023年第2期12卷 503-511页

作者： Shanshan Zhang Xinle xu xu cao Tingting Liu School of Food Science and Engineering Jilin Agricultural UniversityChangchun 130118China Scientific Research Base of Edible Mushroom Processing Technology Integration Ministry of Agriculture and Rural AffairsChangchun 130118China Engineering Research Center of Grain Deep-processing and High-effeciency Utilization of Jilin Province Changchun 130118China Key Laboratory of Technological Innovations for Grain Deep-processing and High-effeciency Utilization of By-products of Jilin Province Changchun 130118China

In this study,Tremella fuciformis residues as raw material,dietary fibers from tremella were prepared by multiple enzymes.The structure of dietary fibers from tremella was studied by Fourier transform infrared(FTIR),X-ray diffraction analysis(XRD)and scanning electron microscopy(SEM).We analyzed their lipidlowering properties in vitro(water holding,oil holding swelling cholesterol and sodium cholate binding capacitises)and the hypolipidemic effects in mice.The results showed that tremella dietary fibers presented the infrared absorption spectrum characteristics of polysaccharides and the characteristic diffraction peaks of cellulose type I.SEM results indicated that the surface of insoluble dietary fiber(IDF)was porous,while the soluble dietary fiber(SDF)was relatively compact and spongy.IDF exhibited significantly higher water holding,oil holding,and swelling binding capacities than the corresponding SDF.However,SDF exhibited significantly higher viscosity than IDF.The results showed tremella dietary fibers were significant in swelling,water holding and oil holding,cholesterol and bile acids.In vivo experiment results in mice indicated that SDF has the best effect on hyperlipidemia mice than IDF and total dietary fiber(TDF).SDF showed that the total cholesterol(TC),triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)contents dropped by 28.33%,18.65%,and 48.97%,respectively,while high density lipoprotein cholesterol(HDL-C)content increased by 43.80%.Compared with the high-fat control(HCM)group,the arteriosclerosis index(AI)and liver index(LI)of the SDF group mice showed significant differences,indicating that SDF has a good auxiliary effect of lowering blood lipids.The administration of tremella fibers improved the lipid metabolism disorderly situation of hyperlipidemia mice.These results provide a reference for further research and rational development of T.fuciformis.

关键词： Tremella fuciformis Dietary fiber Structural characterization Hypolipidemic effects

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Multi-omics-driven development of alternative crops for natural rubber production

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Journal of Integrative Agriculture 2023年第4期22卷 959-971页

作者： YANG Ning YANG Dan-dan YU xu-chen xu cao State Key Laboratory of Plant Genomics National Center for Plant Gene Research(Beijing)Institute of Genetics and Developmental BiologyThe Innovative Academy of Seed DesignChinese Academy of SciencesBeijing 100101P.R.China CAS-JIC Centre of Excellence for Plant and Microbial Science(CEPAMS) Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101P.R.China University of Chinese Academy of Sciences Beijing 100049P.R.China

Natural rubber(NR)is an irreplaceable biopolymer of economic and strategic importance owing to its unique physical and chemical properties.The Parárubber tree(Hevea brasiliensis(Willd.ex A.Juss.)Müll.Arg.)is currently the exclusive commercial source of NR,and it is primarily grown in plantations restricted to the tropical and subtropical areas of Southeast Asia.However,current Parárubber production barely meets the sharply increasing global industrial demand for rubber.Petroleum-based synthetic rubber(SR)has been used to supplement the shortage of NR but its industrial performance is not comparable to that of NR.Thus,there is an urgent need to develop new productive rubber crops with broader environmental adaptability.This review summarizes the current research progress on alternative rubberproducing plants,including horticultural plants(Taraxacum kok-saghyz Rodin and Lactuca L.species),woody plants(Parthenium argentatum A.Gray and Eucommia ulmoides Oliv.),and other plant species with potential for NR production.With an emphasis on the molecular basis of NR biosynthesis revealed by a multi-omics approach,we highlight new integrative strategies and biotechnologies for exploring the mechanism of NR biosynthesis with a broader scope,which may accelerate the breeding and improvement of new rubber crops.

关键词： natural rubber multi-omics genomics transcriptomics proteomics new crops

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Sialylation of TLR2 initiates osteoclast fusion

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Bone Research 2022年第2期10卷 286-296页

作者： Ce Dou Gehua Zhen Yang Dan Mei Wan Nathachit Limjunyawong xu cao Department of Orthopedic Surgery Institute of Cell Engineering and Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreMDUSA The Solomon H.Snyder Department of Neuroscience Johns Hopkins University School of MedicineBaltimoreMDUSA

The molecular control of osteoclast formation is still not clearly elucidated. Here, we show that a process of cell recognition mediated by Siglec15-TLR2 binding is indispensable and occurs prior to cell fusion in RANKL-mediated osteoclastogenesis. Siglec15 has been shown to regulate osteoclastic bone resorption. However, the receptor for Siglec15 has not been identified, and the signaling mechanism involving Siglec15 in osteoclast function remains unclear. We found that Siglec15 bound sialylated TLR2 as its receptor and that the binding of sialylated TLR2 to Siglec15 in macrophages committed to the osteoclast-lineage initiated cell fusion for osteoclast formation, in which sialic acid was transferred by the sialyltransferase ST3 Gal1. Interestingly, the expression of Siglec15 in macrophages was activated by M-CSF, whereas ST3 Gal1 expression was induced by RANKL. Both Siglec15-specific deletion in macrophages and intrafemoral injection of sialidase abrogated cell recognition and reduced subsequent cell fusion for the formation of osteoclasts, resulting in increased bone formation in mice. Thus, our results reveal that cell recognition mediated by the binding of sialylated TLR2 to Siglec15 initiates cell fusion for osteoclast formation.

关键词： osteoclast TLR2 injection

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Neutralization of excessive levels of active TGF-β1 reduces MSC recruitment and differentiation to mitigate peritendinous adhesion

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Bone Research 2023年第2期11卷 368-383页

作者： Yu Sheng Li Xiao Wang Bo Hu Qi Sun Mei Wan Andrew Carr Shen Liu xu cao Department of Orthopedic Surgery The Johns Hopkins University School of MedicineBaltimoreMD21205USA Nuffield Department of Orthopedics Rheumatology and Musculoskeletal SciencesBotnar Research CentreUniversity of OxfordWindmill RoadOxford OX 37 LDUK

PPeritendinous adhesion formation(PAF)can substantially limit the range of motion of digits.However,the origin of myofibroblasts in PAF tissues is still unclear.In this study,we found that the concentration of active TGF-β1 and the numbers of macrophages,mesenchymal stromal cells(MSCs),and myofibroblasts in human and mouse adhesion tissues were increased.Furthermore,knockout of TGF-β1 in macrophages or TGF-β1R2 in MSCs inhibited PAF by reducing MSC and myofibroblast infiltration and collagenⅠandⅢdeposition,respectively.Moreover,we found that MSCs differentiated into myofibroblasts to form adhesion tissues.Systemic injection of the TGF-β–neutralizing antibody 1D11 during the granulation formation stage of PAF significantly reduced the infiltration of MSCs and myofibroblasts and,subsequently,PAF.These results suggest that macrophage-derived TGF-β1 recruits MSCs to form myofibroblasts in peritendinous adhesions.An improved understanding of PAF mechanisms could help identify a potential therapeutic strategy.

关键词： inhibited injection MSC

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Mechanisms of bone pain:Progress in research from bench to bedside

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Bone Research 2022年第3期10卷 440-453页

作者： Gehua Zhen Yuhan Fu Chi Zhang Neil C.Ford Xiaojun Wu Qichao Wu Dong Yan xueming Chen xu cao Yun Guan Department of Orthopedics Johns Hopkins UniversitySchool of MedicineBaltimoreMD 21205USA Department of Anesthesiology and Critical Care Medicine Johns Hopkins UniversitySchool of MedicineBaltimoreMD 21205USA Division of Pathology Sibley Memorial Hospital WashingtonWashingtonDC 20016USA Department of Oncology Beijing Luhe HospitalCapital Medical UniversityBeijing 100149China Department of Orthopedics Beijing Luhe HospitalCapital Medical UniversityBeijing 100149China Department of Neurological Surgery Johns Hopkins UniversitySchool of MedicineBaltimoreMD 21205USA

The field of research on pain originating from various bone diseases is expanding rapidly, with new mechanisms and targets asserting both peripheral and central sites of action. The scope of research is broadening from bone biology to neuroscience,neuroendocrinology, and immunology. In particular, the roles of primary sensory neurons and non-neuronal cells in the peripheral tissues as important targets for bone pain treatment are under extensive investigation in both pre-clinical and clinical settings. An understanding of the peripheral mechanisms underlying pain conditions associated with various bone diseases will aid in the appropriate application and development of optimal strategies for not only managing bone pain symptoms but also improving bone repairing and remodeling, which potentially cures the underlying etiology for long-term functional recovery. In this review, we focus on advances in important preclinical studies of significant bone pain conditions in the past 5 years that indicated new peripheral neuronal and non-neuronal mechanisms, novel targets for potential clinical interventions, and future directions of research.

关键词： pain clinical diseases

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RANKL-RANK signaling regulates osteoblast differentiation and bone formation

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Bone Research 2018年第4期6卷 426-427页

作者： xu cao Department of Orthopedic Surgery Johns Hopkins University School of Medicine

In the recent two decades, it has been well elucidated that receptor activator of nuclear factor-κB ligand (RANKL;also known as TNFSF11) binding to its receptor RANK (also known as TNFRSF11A) drives osteoclast development as the crucial signaling pathway.1-3 However, accumulating evidence also implies that osteoblastic RANKL regulates osteoblastogenesis.4-6 The studies “RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation” by Chen et al.

关键词： decades RANKL accumulating

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Predicting assembly mode of membraneless organelles by a FRET-based crowding sensor

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3225-3227页

作者： Feng Chen Siyuan Shen xu cao Liang Zhang Lunxu Liu Daoke Yang Yunyu Shi Wei He xuebiao Yao Dan Liu MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics Hefei National Research Center for Physical Sciences at the MicroscaleDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230027China Department of Thoracic Surgery/Institute of Thoracic Oncology West China HospitalSichuan UniversityChengdu 610065China Cancer Hospital of the First Affiliated Hospital of Zhengzhou University Zhengzhou 450052China

Dear Editor,Biomacromolecules aggregate to form membraneless organelles(MLOs)via phase separation has been observed in a variety of physiological processes over the last decade.1 However,the molecular basis of biomacromolecule phase separation in cells and assembly modes of this process remain largely unknown due to a lack of available experimental methods.The dynamics of different MLOs vary widely.

关键词： separation methods mode

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Detrimental impact of hyperlipidemia on the peripheral nervous system A novel target of medical epidemiological and fundamental research study

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Neural Regeneration Research 2012年第5期7卷 392-399页

作者： Song Wu xu cao Rongzhen He Kun Xiong Department of Orthopedics Third Xiangya Hospital of Central South University Changsha 410013 Hunan Province China Clinical Medicine Eight-year Program 01 Class 07 Grade Central South University Changsha 410013 Hunan Province China Department of Anatomy and Neurobiology Xiangya Medical School of Central South University Changsha 410013 Hunan Province China

Recently, epidemiological studies on the etiology of peripheral neuropathies have revealed that hyperlipidemia is a novel risk factor. Plasma lipid levels were confirmed to be associated with the incidence of many peripheral neuropathies including axonal distal polyneuropathy, vision and hearing loss, motor nerve system lesions and sympathetic nerve system dysfunction. Moreover, different lipid components such as cholesterol, triacylglycerols and lipoprotein are involved in the pathogenesis of these neuropathies. This review aimed to discuss the effect of hyperlipidemia on the peripheral nervous system and its association with peripheral neuropathies. Furthermore, a detailed discussion focusing on the explicit mechanisms related to hyperlipidemia-induced peripheral neuropathies is presented here. These mechanisms, including intracellular oxidative stress, inflammatory lesions, ischemia and dysregulation of local lipid metabolism, share pathways and interact mutually. In addition, we examined current information on clinical trials to prevent and treat peripheral neuropathies caused by hyperlipidemia, with a predictive discussion regarding the orientation of future investigations.

关键词： hyperlipidemia peripheral nervous system neuropathy reviews

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