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Ultrafine-grained Nb-Cu immiscible alloy implants for hard tissue repair:Fabrication,characterization,and in vitro and in vivo evaluation

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Journal of Materials Science & Technology 2022年第32期127卷 214-224页

作者： Chuanxin Zhong Dingshan Liang Tian Wan Shan He Lu Yang Ju Fang Ge Zhang Fuzeng Ren Department of Materials Science and Engineering Southern University of Science and TechnologyShenzhen 518055China law sau fai institute for advancing translational medicine in bone and joint diseases School of Chinese MedicineHong Kong Baptist UniversityChina Hong Kong Special Administrative Region

The biocompatible metallic implants with strong osteointegration often lack the ability of *** biocompatible niobium(Nb)containing the antibacterial copper(Cu),the obtained Nb-Cu alloy,could be a potential candidate to solve this *** test this hypothesis,ultrafine-grained Nb-Cu immiscible alloys were fabricated via mechanical alloying and spark plasma *** aim of this study was to investigate the microstructure,mechanical properties,magnetic susceptibility,corrosion behavior,ion release,and the bactericidal activity,biocompatibility and osteogenic potential of the Nb-Cu alloys in vitro and their osteogenesis and osteointegration ability in vivo with a comparison with pure *** rat cranial defect model and the bone screws insertion in rabbit femoral bone were used to evaluate the osteogenesis and osteointegration ability,*** results showed that after the addition of 3 wt.%of Cu,the compressive strength was significantly improved from 1.57 GPa to 2.21 GPa and the magnetic susceptibility slightly *** Nb-3 wt.%Cu(Nb-3Cu)alloy exhibited higher corrosion resistance than pure Nb in Hank’s solution and strong bactericidal activity against both *** and *** vitro,the Nb-3Cu alloy showed comparable biocompatibility with pure *** addition of 3 wt.%Cu also significantly enhanced the expression of osteogenesis-related genes(RUNX2,ALP,COLA1 and OCN)of *** vivo,the Nb-3Cu alloy promoted bone regeneration at the defect sites and showed enhanced osteointegration after 12 weeks of *** a good combination of high mechanical strength and corrosion resistance,strong antibacterial activity and improved osteogenesis and osseointegration ability enables the present Nb-3Cu alloy a promising candidate for heavy load-bearing hard tissue repair.

关键词： Nb-Cu immiscible alloy Antibacterial Osteogenesis bone screws Osteointegration

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Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

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International Journal of Oral Science 2022年第4期14卷 479-488页

作者： Bingdong Sui Jin Liu Chenxi Zheng Lei Dang Ji Chen Yuan Cao Kaichao Zhang Lu Liu Minyan Dang Liqiang Zhang Nan Chen Tao He Kun Xuan Fang Jin Ge Zhang Yan Jin Chenghu Hu State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral diseases and Shaanxi International joint Research Center for Oral diseases Center for Tissue EngineeringSchool of StomatologyThe Fourth Military Medical UniversityXi'anChina law sau fai institute for advancing translational medicine in bone and joint diseases School of Chinese MedicineHong Kong Baptist UniversityHong Kong SARChina Xi'an Key Laboratory of Stem Cell and Regenerative medicine Institute of Medical ResearchNorthwestern Polytechnical UniversityXianChina Xi'an institute of Tssue Engineering and Regenerative medicine XianChina Department of Biochemistry and Molecular Biology School of Basic Medical SciencesXi'an Jiaotong UniversityXi'anChina

Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss,but the mechanisms and therapeutics remain incompletely ***,we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized micro RNA response and efficient *** discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-adrenergic receptor(β2AR)signaling,critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4(Pdcd4),and mediated detrimental effects of both isoproterenol(ISO)and chronic variable stress(CVS)on ***,without affecting osteoblastic bone formation,bone protection against ISO and CVS was sufficiently achieved by a(D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic mi R-21 or by clinically relevant drugs to suppress ***,these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.

关键词： osteoclast pathogenesis homeostasis

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Drug discovery of sclerostin inhibitors

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2150-2170页

作者： Sifan Yu Dijie Li Ning Zhang Shuaijian Ni Meiheng Sun Luyao Wang Huan Xiao Dingdong Liu Jin Liu Yuanyuan Yu Zongkang Zhang Samuel Tin Yui Yeung Shu Zhang Aiping Lu Zhenlin Zhang Baoting Zhang Ge Zhang law sau fai institute for advancing translational medicine in bone and joint diseases School of Chinese MedicineHong Kong Baptist UniversityKowloon TsaiHong Kong 999077China institute of Integrated Bioinfomedicine and translational Science School of Chinese MedicineHong Kong Baptist UniversityKowloon TsaiHong Kong 999077China institute of Precision medicine and Innovative Drug Discovery HKBU Institute for Research and Continuing EducationShenzhen 518000China School of Chinese medicine Faculty of Medicinethe Chinese University of Hong KongHong Kong 999077China The Key Laboratory of Aerospace medicine Ministry of EducationAir Force Medical UniversityXi’an 710000China Shanghai Clinical Research Center of bone Disease Department of Osteoporosis and Bone DiseasesShanghai Jiao Tong University Afﬁliated Sixth People’s HospitalShanghai 200000China

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

关键词： Sclerostin WNT signalling pathway Sclerostin inhibitors Antibody bone diseases Aptamer Small molecule inhibitors Artificial intelligence

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Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

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Signal Transduction and Targeted Therapy 2021年第1期6卷 131-143页

作者： Xuekun Fu Bo Zhou Qinnan Yan Chu Tao Lei Qin Xiaohao Wu Sixiong Lin Sheng Chen Yumei Lai Xuenong Zou Zengwu Shao Meiqing Wang Di Chen Wenfei Jin Youqiang Song Huiling Cao Ge Zhang Guozhi Xiao School of medicine Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Researchand Shenzhen Key Laboratory of Cell MicroenvironmentSouthern University of Science and Technology1088 Xue Yuan Road518055 ShenzhenGuangdongChina law sau fai institute for advancing translational medicine in bone and joint diseases School of Chinese MedicineHong Kong Baptist University999077 Hong KongSARChina Department of Biology Southern University of Science and Technology518055 ShenzhenChina School of Biomedical Sciences University of Hong Kong21 Sassoon RoadHong KongChina Department of Spine Surgery Orthopedic Research InstituteThe First Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Orthopedics and Traumatology510080 GuangzhouChina Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and Technology430022 WuhanChina Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA State Key Laboratory of Military Stomatology National Clinical Research Center for Oral DiseasesShanxi International Joint Research Center for Oral DiseasesDepartment of Oral Anatomy and Physiology and TMDSchool of Stomatologythe Fourth Military Medical University145 Changle West RoadXi’anChina Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of Sciences518055 ShenzhenChina

In vertebrates,the type 1 parathyroid hormone receptor(PTH1R)is a critical regulator of skeletal development and homeostasis;however,how it is modulated is incompletely *** we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult ***-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts,but not mesenchymal stem cells,chondrocytes and fibroblasts,in non-hematopoietic bone marrow cells,with concomitant depletion of osteoblasts on the bone surfaces,especially those stimulated by ***,haploinsufficiency of Kindlin-2 and Pth1r genes,but not that of either gene,in mice significantly decreases basal and,to a larger extent,PTH-stimulated bone mass,supporting the notion that both factors function in the same genetic ***,Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα.Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in ***,PTH promotes Kindlin-2 expression in vitro and in vivo,thus creating a positive feedback regulatory ***,estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized ***,we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis.

关键词： homeostasis Kindlin skeletal

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