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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical models.Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition.RNA sequencing of human and mouse tissue supported these findings.The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts.The results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within lesions.These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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ROS-responsive hydrogels with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs for the repair of MRSA-infected wounds

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Regenerative Biomaterials 2024年第1期3卷 119-131页

作者： Bowen Qiao Jiaxin Wang Lipeng Qiao Aziz Maleki Yongping Liang Baolin Guo Key Laboratory of Shaanxi Province for craniofacial Precision Medicine research College of StomatologyXi’an Jiaotong UniversityXi’an 710049China State Key Laboratory for Mechanical Behavior of Materials Frontier Institute of Science and TechnologyXi’an Jiaotong UniversityXi’an 710049China Zanjan Pharmaceutical Nanotechnology research center(ZPNRC) Zanjan 45139-56184Iran Department of Orthopaedics The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061People’s Republic of China

For the treatment of MRSA-infected wounds,the spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs is a promising strategy.In this study,ROS-responsive HA-PBA/PVA(HPA)hydrogel was prepared by phenylborate ester bond cross-linking between hyaluronic acid-grafted 3-amino phenylboronic acid(HA-PBA)and polyvinyl alcohol(PVA)to achieve spatiotemporally controlled release of two kinds of drug to treat MRSA-infected wound.The hydrophilic antibiotic moxifloxacin(M)was directly loaded in the hydrogel.And hydrophobic curcumin(Cur)with anti-inflammatory function was first mixed with Pluronic F127(PF)to form Cur-encapsulated PF micelles(Cur-PF),and then loaded into the HPA hydrogel.Due to the different hydrophilic and hydrophobic nature of moxifloxacin and Cur and their different existing forms in the HPA hydrogel,the final HPA/M&Cur-PF hydrogel can achieve different spatiotemporally sequential delivery of the two drugs.In addition,the swelling,degradation,self-healing,antibacterial,anti-inflammatory,antioxidant property,and biocompatibility of hydrogels were tested.Finally,in the MRSA-infected mouse skin wound,the hydrogel-treated group showed faster wound closure,less inflammation and more collagen deposition.Immunofluorescence experiments further confirmed that the hydrogel promoted better repair by reducing inflammation(TNF-a)and promoting vascular(VEGF)regeneration.In conclusion,this HPA/M&CurPF hydrogel that can spatiotemporally sequential deliver antibacterial and anti-inflammatory drugs showed great potential for the repair of MRSA-infected skin wounds.

关键词： MRSA-infected wounds spatiotemporally sequential delivery antibacterial anti-inflammatory

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Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

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Journal of Genetics and Genomics 2024年第2期51卷 222-229页

作者： Wenbin Huang Shiying Zhang Jiuxiang Lin Yi Ding Nan Jiang Jieni Zhang Huaxiang Zhao Feng Chen Department of Orthodontics Peking University School and Hospital of StomatologyBeijing100081China Key Laboratory of Shaanxi Province for craniofacial Precision Medicine research College of StomatologyXi’an Jiaotong UniversityXi’anShaanxi710004China Guangdong Provincial High-level Clinical Key Specialty Guangdong Province Engineering Research Center of Oral Disease Diagnosis and TreatmentDepartment of OrthodonticsStomatological CenterPeking University Shenzhen HospitalShenzhen Peking University-The Hong Kong University of Science and Technology Medical CenterShenzhenGuangdong 518036China Department of Physiology and Pathophysiology School of Basic Medical SciencesXi'an Jiaotong UniversityXi'anShaanxi710049China National center for Stomatology National Clinical Research Center for Oral DiseasesNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory for Digital StomatologyResearch Center of Engineering and Technology for Computerized Dentistry Ministry of HealthNMPA Key Laboratory for Dental MaterialsBeijing100101China Central Laboratory Peking University School and Hospital of StomatologyBeijing100081China

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

关键词： Or ofacial clefts FLNB Loss-of-function mutati on Cleft palate Filamin B Actin flannent Knockout mouse

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Bacteria-responsive programmed self-activating antibacterial hydrogel to remodel regeneration microenvironment for infected wound healing

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National Science Review 2024年第4期11卷 254-270页

作者： Yutong Yang Jiaxin Wang Shengfei Huang Meng Li Jueying Chen Dandan Pei Zhen Tang Baolin Guo State Key Laboratory for Mechanical Behavior of Materials and Frontier Institute of Science and Technology and Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine ResearchCollege of Stomatology Xi'an Jiaotong University Department of Orthopedics Tangdu Hospital Fourth Military Medical University Department of Orthopedics The First Affiliated Hospital of Xi'an Jiaotong University

There is still an urgent need to develop hydrogels with intelligent antibacterial ability to achieve on-demand treatment of infected wounds and accelerate wound healing by improving the regeneration microenvironment. We proposed a strategy of hydrogel wound dressing with bacteria-responsive self-activating antibacterial property and multiple nanozyme activities to remodel the regeneration microenvironment in order to significantly promote infected wound healing. Specifically, p H-responsive H2O2self-supplying composite nanozyme（MSCO） and p H/enzyme-sensitive bacteria-responsive triblock micelles encapsulated with lactate oxidase（PPEL） were prepared and encapsulated in hydrogels composed of L-arginine-modified chitosan（CA） and phenylboronic acid-modified oxidized dextran（ODP） to form a cascade bacteria-responsive self-activating antibacterial composite hydrogel platform. The hydrogels respond to multifactorial changes of the bacterial metabolic microenvironment to achieve on-demand antibacterial and biofilm eradication through transformation of bacterial metabolites, and chemodynamic therapy enhanced by nanozyme activity in conjunction with self-driven nitric oxide（NO） release. The composite hydrogel showed 'self-diagnostic' treatment for changes in the wound microenvironment.Through self-activating antibacterial therapy in the infection stage to self-adaptive oxidative stress relief and angiogenesis in the post-infection stage, it promotes wound closure, accelerates wound collagen deposition and angiogenesis, and completely improves the microenvironment of infected wound regeneration, which provides a new method for the design of intelligent wound dressings.

关键词： bacterial response hydrogel dressing multiple nanozyme activity biofilm elimination infected motion wound healing

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Autophagy and circadian rhythms:interactions and clinical implications

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BIOCELL 2024年第1期48卷 33-45页

作者： TIANKAI DI ZHIFEI ZHOU FEN LIU YUJIANG CHEN LULU WANG State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral DiseasesShaanxi Clinical Research Center for Oral DiseasesDepartment of Pediatric DentistrySchool of StomatologyThe Fourth Military Medical UniversityXi’an710032China Department of Stomatology The 969th HospitalJoint Logistics Support Force of the Chinese People’s Liberation ArmyHohhot010000China Department of Stomatology General Hospital of Tibetan Military CommandLhasa850000China Key Laboratory of Shaanxi Province for craniofacial Precision Medicine research Clinical Research Center of Shaanxi Province for Dental and Maxillofacial DiseasesDepartment of Pediatric DentistryCollege of StomatologyXi’an Jiaotong UniversityXi’an710000China Department of Neurobiology and Institute of Neurosciences School of Basic MedicineFourth Military Medical UniversityXi’an710032China

Autophagy is a widespread biological process that controls cellular growth,survival,development,and death.Circadian rhythm is a recurring reaction of living organisms and behaviors to variations in surrounding brightness and obscurity.Most of the fundamental physiological processes in mammals,such as the sleep-wake pattern and the rhythm of nutrition and energy metabolism,are governed by circadian rhythms.research has indicated that autophagy exhibits a specific circadian pattern in both normal and abnormal conditions.Autophagy can modulate circadian rhythms by breaking down proteins that regulate the circadian clock.The potential regulatory connection between the two has been a popular subject of clinical and fundamental research.Understanding the interaction between circadian rhythm and autophagy could potentially lead to the development of novel approaches for disease treatment in the future.The present analysis presented a summary of the molecular processes implicated in the interplay between autophagy and circadian rhythm,as well as the pathological importance of the disrupted regulatory association between these two phenomena.

关键词： Autophagy Circadian rhythms Mechanism Application

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A Self-Healing Optoacoustic Patch with High Damage Threshold and Conversion Efficiency for Biomedical Applications

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Nano-Micro Letters 2024年第7期16卷 31-45页

作者： Tao Zhang Cheng-Hui Li Wenbo Li Zhen Wang Zhongya Gu Jiapu Li Junru Yuan Jun Ou-Yang Xiaofei Yang Benpeng Zhu School of Integrated Circuit Wuhan National Laboratory for OptoelectronicsHuazhong University of Science and TechnologyWuhan 430074People’s Republic of China State Key Laboratory of Coordination Chemistry Collaborative Innovation Center of Advanced MicrostructuresSchool of Chemistry and Chemical EngineeringNanjing UniversityNanjing 210093People’s Republic of China National Institute of Dental and craniofacial research(NIDCR) National Institutes of Health(NIH)35A Convent DriveBethesdaMD 20892USA Department of Neurology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030People’s Republic of China

Compared with traditional piezoelectric ultrasonic devices,optoacoustic devices have unique advantages such as a simple preparation process,anti-electromagnetic interference,and wireless long-distance power supply.However,current optoacoustic devices remain limited due to a low damage threshold and energy conversion efficiency,which seriously hinder their widespread applications.In this study,using a self-healing polydimethylsiloxane(PDMS,Fe-Hpdca-PDMS)and carbon nanotube composite,a flexible optoacoustic patch is developed,which possesses the self-healing capability at room temperature,and can even recover from damage induced by cutting or laser irradiation.Moreover,this patch can generate high-intensity ultrasound(>25 MPa)without the focusing structure.The laser damage threshold is greater than 183.44 mJ cm^(-2),and the optoacoustic energy conversion efficiency reaches a major achievement at 10.66×10^(-3),compared with other carbon-based nanomaterials and PDMS composites.This patch is also been successfully examined in the application of acoustic flow,thrombolysis,and wireless energy harvesting.All findings in this study provides new insight into designing and fabricating of novel ultrasound devices for biomedical applications.

关键词： Optoacoustic Self-healing PDMS Acoustic flow Thrombolytic Wireless energy harvesting

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氨基酸基防污可注射自融合水凝胶的制备及其在术后防粘连中的应用

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Science China Materials 2024年第5期67卷 1521-1532页

作者：李萌张梦园刘正谢瑞琳杨宇轩申锴翔杨爱民成一龙 Engineering research center of Energy Storage Materials and Devices Ministry of EducationSchool of ChemistryXi’an Jiaotong UniversityXi’an710049China Key Laboratory of Shaanxi Province for craniofacial Precision Medicine research College of StomatologyXi’an Jiaotong UniversityXi’an710049China Department of Nuclear Medicine the First Affiliated Hospital of ChinaXi’an Jiaotong UniversityXi’an710049China

设计和制备具有优异防污能力的可注射防粘连材料对预防手术后组织和器官的粘连具有重要的意义.在此,我们将含有羟基的氨基酸衍生物引入水凝胶的制备中,通过N-丙烯酰丝氨酸(ASer)的自由基聚合制备了一种新型的氢键交联水凝胶(PASer).结... 详细信息

设计和制备具有优异防污能力的可注射防粘连材料对预防手术后组织和器官的粘连具有重要的意义.在此,我们将含有羟基的氨基酸衍生物引入水凝胶的制备中,通过N-丙烯酰丝氨酸(ASer)的自由基聚合制备了一种新型的氢键交联水凝胶(PASer).结果发现一个甲基取代基的存在会对分子间氢键相互作用产生明显的影响:与聚(N-丙烯酰苏氨酸)(PAThr)水凝胶相比,PASer水凝胶具有较低的成胶浓度和增强的力学性能.值得一提的是,亲水性羟基使PASer水凝胶能够有效抵抗蛋白质吸附和细胞粘附.PASer水凝胶具有优异的力学性能、可注射性、自融合性、良好的生物相容性和适宜的体内停留时间,符合临床对术后抗粘连材料的要求.体内研究实验结果表明,PASer水凝胶在建立的小鼠腹壁缺损模型中可以有效预防术后腹膜粘连发生.

关键词： hydrogel injectability antifouling amino acid abdominal adhesion

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Bioinspired mineral-in-shell nanoarchitectonics:Functional empowerment of mineral precursors for guiding intradentinal mineralization

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Nano research 2024年第5期17卷 4338-4349页

作者： Xiaoran Zheng Yang Liu Mingjing Li Yuyan Li Wanshan Gao Rongmin Qiu Jiaqi Xing Jiaojiao Yang Yantao Chen Xinyuan Xu Mingming Ding Jun Luo Jianshu Li College of Polymer Science and Engineering State Key Laboratory of Polymer Materials EngineeringSichuan UniversityChengdu 610065China College of Stomatology Hospital of Stomatology Guangxi Medical UniversityGuangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and ReconstructionGuangxi Clinical Research Center for Craniofacial DeformityGuangxi Key Laboratory of Oral and Maxillofacial Surgery Disease TreatmentGuangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious DiseasesNanning 530021China State Key Laboratory of Oral Diseases West China Hospital of StomatologySichuan UniversityChengdu 610041China Shenzhen Key Laboratory of Environmental Chemistry and Ecological Remediation College of Chemistry and Environmental EngineeringShenzhen UniversityShenzhen 518060China Med-X center for Material Sichuan UniversityChengdu 610041China

Effective mineralization of biological structures poses a significant challenge in hard tissue engineering as it necessitates overcoming geometric complexities and multistep biomineralization processes.In this regard,we propose“mineral-in-shell nanoarchitectonics”,inspired by the nanostructure of matrix vesicles,which can influence multiple mineralization pathways.Our nanostructural design empowers mineral precursors with tailorable properties through encapsulating amorphous calcium phosphate within a multifunctional tannic acid(TA)and silk fibroin(SF)nanoshell.The bioinspired nanosystem facilitates efficient recruitment of mineral precursors throughout the dentin structures,followed by large-scale intradentinal mineralization both in vitro and in vivo,which provides persistent protection against external stimuli.Theoretical simulations combined with experimental studies attribute the success of intradentinal mineralization to the TA-SF nanoshell,which exhibits a strong affinity for the dentin structure,stabilizing amorphous precursors and thereby facilitating concomitant mineral formation.Overall,this bioinspired mineral-in-shell nanoarchitectonics shows a promising prospect for hard tissue repair and serves as a blueprint for next-generation biomineralization-associated materials.

关键词： mineral-in-shell nanohybrids self-assembly biomineralization dentinal tubule occlusion dental hypersensitivity

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A simplified noncryogenic strategy to transport mesenchymal stem cells: Potential applications in cell therapy and regenerative medicine

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Genes & Diseases 2024年第3期11卷 26-29页

作者： Xiangyu Dong Yannian Gou Meichun Guo Jiamin Zhong Aohua Li Ailing Hao Wei Zeng Rex C.Haydon Hue H.Luu Russell R.Reid Tongchuan He Yan Xu Jiaming Fan Ministry of Education Key Laboratory of Diagnostic Medicine And Department of Clinical BiochemistryCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Laboratory of craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Institute of Sports Medicine Beijing Key Laboratory of Sports InjuriesPeking University Third HospitalBejing 100191China

With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport strategies.Except for autologous stem cell-based therapies,allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe,efficient,and reliable cell preservation and transport methods.

关键词： transport methods simplified

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

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Genes & Diseases 2024年第1期11卷 103-134页

作者： Kevin Qin Michael Yu Jiaming Fan Hongwei Wang Piao Zhao Guozhi Zhaoo Wei Zeng Connie Chen Yonghui Wang Annie Wang Zander Schwartz Jeffrey Hong Lily Song William Wagstaff Rex C.Haydon Hue H.Luu Sherwin H.Ho Jason Strelzow Russell R.Reid Tong-Chuan He Lewis L.Shi Chicago Medical School Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA Laboratory of craniofacial Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical pathway.Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling pathways.This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes.Dys-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic lethality.The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments.However,both stimulatory and inhibitory treatments come with potential risks that need to be addressed.This review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt signaling.It thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+pathway.Further description involved each of its components and their involvement in other cellular processes.Finally,this review explained the various other pathways and processes that crosstalk with Wnt signaling.

关键词： β-catenin Canonical Wnt Noncanonical Wnt Signal transduction Signaling crosstalk

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