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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 *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** 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 *** 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 *** sequencing of human and mouse tissue supported these *** 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 *** 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 *** 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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Meeting report:a hard look at the state of enamel research

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International Journal of Oral Science 2017年第4期9卷 193-199页

作者： ophir d klein olivier duverger wendy shaw rodrigo s lacruz derk joester janet moradian-oldak megan k pugach j timothy wright sarah e millar ashok b kulkarni john d bartlett thomas gh diekwisch pamela den besten james p simmer program in craniofacial biology and department of orofacial sciences university of californiasan franciscoSan FranciscoUSA department of pediatrics and institute for human genetics university of californiasan franciscoSan FranciscoUSA laboratory of skin biology national institute of arthritis and muscular and skin diseasesnational institutes of healthBethesdaUSA physical science division pacific northwest national laboratoriesRichlandUSA department of basic science and craniofacial biology new york university college of dentistryNewYorkUSA department of materials science and engineering northwestern universityevanstonusaEvanstonUSA center for craniofacial molecular biology herman ostrow school of dentistryuniversity of southern californiaLos AngelesUSA the forsyth institute CambridgeUSA department of developmental biology harvard school of dental medicineBostonUSA department of pediatric dentistry university of north caroline school of dentistryChapel HillUSA departments of dermatology and cel&developmental biology perelman school of medicineand department of anatomy&cell biologyschool of dental medicineuniversity of pennsylvaniaPhiladelphiaUSA functional genomics section national institute of dental and craniofacial researchBethesdaUSA division of biosciences ohio state universitycollege of dentistryColumbusUSA department of periodontics and center for craniofacial research and diagnosis texas a&m university college of dentistryDallasUSA center for children’s oral health research and department of orofacial sciences university of californiasan franciscoSan FranciscoUSA biologic and materials sciences and division of prosthodontics university of michiganAnn ArborUSA

The Encouraging Novel Amelogenesis Models and Ex vivo cell Lines （ENAMEL） Development workshop was held on 23 June 2017 at the Bethesda headquarters of the National institute of Dental and craniofacial Research （NIDCR）. Discussion topics included model organisms, stem cells/cell lines, and tissues/3D cell culture/organoids. Scientists from a number of disciplines, representing institutions from across the United States, gathered to discuss advances in our understanding of enamel, as well as future directions for the field.

关键词： enamel mineralized tissue mineralization ameloblast stem cell

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Application of platelet-rich plasma with stem cells in bone and periodontal tissue engineering

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Bone Research 2016年第4期4卷 185-205页

作者： Gabriela Fernandes Shuying Yang Department of Oral biology School of Dental Medicine University at Buffalo The State University of New York developmental genomics Group New York State Center of Excellence in Bioinformatics and Life Sciences University at Buffalo The State University of New York Department of Anatomy & Cell biology School of Dental Medicine University of Pennsylvania

Presently, there is a high paucity of bone grafts in the United States and worldwide. Regenerating bone is of prime concern due to the current demand of bone grafts and the increasing number of diseases causing bone loss. Autogenous bone is the present gold standard of bone regeneration. However, disadvantages like donor site morbidity and its decreased availability limit its use. Even allografts and synthetic grafting materials have their own limitations. As certain specific stem cells can be directed to differentiate into an osteoblastic lineage in the presence of growth factors(GFs), it makes stem cells the ideal agents for bone ***, platelet-rich plasma(PRP), which can be easily isolated from whole blood, is often used for bone regeneration, wound healing and bone defect repair. When stem cells are combined with PRP in the presence of GFs, they are able to promote osteogenesis. This review provides in-depth knowledge regarding the use of stem cells and PRP in vitro, in vivo and their application in clinical studies in the future.

关键词： bone cell Application of platelet-rich plasma with stem cells in bone and periodontal tissue engineering BMSCs stem

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Bone morphogenetic protein-9 effectively induces osteogenic differentiation of reversibly immortalized calvarial mesenchymal progenitor cells

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Genes & Diseases 2015年第3期2卷 268-275页

作者： Chad M.Teven Michael T.Rossi Deana S.Shenaq Guillermo A.Ameer Russell R.Reid The Laboratory of craniofacial Development and biology Section of Plastic and Reconstructive SurgeryUniversity of Chicago MedicineChicagoILUSA Department of Biomedical Engineering Northwestern UniversityChicagoILUSA Department of Surgery Northwestern UniversityChicagoILUSA

Critical-sized craniofacial defect repair represents a significant challenge to reconstructive *** strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable *** morphogenetic proteins(BMPs)provide a robust osteoinductive cue to stimulate bony growth and *** studies have suggested that the BMP-9 isoform is particularly effective in promoting osteogenic differentiation of mesenchymal progenitor *** aim of this study is to characterize the osteogenic capacity of BMP-9 on calvarial mesenchymal progenitor cell *** immortalized murine calvarial progenitor cells(iCALs)were infected with adenoviral vectors encoding BMP-9 or GFP and assessed for early and late stages of osteogenic differentiation in vitro and for osteogenic differentiation via in vivo stem cell implantation *** elevations in alkaline phosphatase(ALP)activity,osteocalcin(OCN)mRNA transcription,osteopontin(OPN)protein expression,and matrix mineralization were detected in BMP-treated cells compared to ***,ALP activity was elevated on days 3,7,9,11,and 13 post-infection and OCN mRNA expression was elevated on days 8,10,and 14 in treated ***,treatment groups demonstrated increased OPN protein expression on day 10 and matrix mineralization on day 14 post-infection relative to control ***-9 also facilitated the formation of new bone in vivo as detailed by gross,microcomputed tomography,and histological ***,we concluded that BMP-9 significantly stimulates osteogenic differentiation in iCALs,and should be considered an effective agent for calvarial tissue regeneration.

关键词： Bone morphogenetic protein(BMP) Bone morphogenetic protein-9(BMP-9) Immortalized calvarial cell(iCAL) Mesenchymal progenitor cell Osteogenic capacity Osteogenic differentiation

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KIF3马达分子运送N-cadherin并对发育中的神经上皮的结构起组织作用

KIF3马达分子运送N-cadherin并对发育中的神经上皮的结构起组织作...

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中国细胞生物学学会2005年学术大会、青年学术研讨会

作者：滕俊琳 Tatemitsu Rai Yosuke Tanaka Yosuke Takei Takao Nakata Motoyuki Hirasawa Ashok B．Kulkarni Nobutaka Hirokawa 北京大学生命科学学院 Department of Cell biology and Anatomy Graduate School of Medicine University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan Department of Cell biology and Anatomy Graduate School of Medicine University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan Department of Cell biology and Anatomy Graduate School of Medicine University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan functional genomics section craniofacial developmental biology and regeneration branch National Institute of Dental and craniofacial Research National Institutes of Health Bethesda MD 20892-4326 USA functional genomics section craniofacial developmental biology and regeneration branch National Institute of Dental and craniofacial Research National Institutes of Health Bethesda MD 20892-4326 USA functional genomics section craniofacial developmental biology and regeneration branch National Institute of Dental and craniofacial Research National Institutes of Health Bethesda MD 20892-4326 USA Department of Cell biology and Anatomy Graduate School of Medicine University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan

KIFs(kinesin superfamily proteins)是依赖于微管的马达分子,在细胞内承担膜性细胞器或生物大分子复合物的运输作用。KIF3是由KIF3A／KIF3B／KAP3构成的向微管正极运输膜泡的马达分子。 KAP3(kinsein superfamily-associated prctein 3)为KIF3复合体的非马达亚基,负责调节KIF3马达蛋白与其货物间的相互连接。我们利用Cre／loxP介导的条件性基因靶技术(Cre／loxP-mediated conditional gene targeting strategy),建立了KAP3条件性基因剔除小鼠(conditional knockout mouse)。发现在神经系统的发育过程中,KAP3与维持神经前体细胞分裂和细胞间粘连的平衡相关。KIF3与N-cadherin和β-catenin结合,行使post-Golgi运输N-cadherin的功能。在KAP3缺失的细胞中,N-cadherin的亚细胞定位紊乱。在条件性基因剔除小鼠的脑中,由于N-cadherin不能正常定位而导致神经上皮组织的发育异常,并形成成室管膜瘤样结构。上述结果提示KIF3／KAP3具有抑制肿瘤形成的功能,为成室管膜瘤的研究提供了动物模型。

关键词：神经上皮 N-cadherin

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Secreted frizzled related-protein 2(Sfrp2)deficiency decreases adult skeletal stem cell function in mice

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Bone Research 2021年第4期9卷 606-617页

作者： Luis Fernandez de Castro Brian丄Sworder Byron Mui Kathryn Futrega Agnes Berendsen Matthew D.Phillips Nathan J.Burbach Natasha Cherman Sergei Kuznetsov Yankel Gabet Kenn Holmbeck Pamela G.Robey Skeletal biology section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthDepartment of Health and Human ServicesNational Institutes of HealthBethesdaMDUSA Department of Molecular Medicine Boston UniversityBostonMAUSA School of Dentistry University of Minnesota-Twin CitiesMinneapolisMNUSA Department of Anatomy and Anthropology Sackler Faculty of MedicineTel Aviv UniversityTel Aviv-YafoIsrael

In a previous transcriptomic study of human bone marrow stromal cells(BMSCs,also known as bone marrow-derived^mesenchymal stem cells#,)/SFRP2 was highly over-represented in a subset of multipotent BMSCs(skeletal stem cells,SSCs),which recreate a bone/marrow organ in an in vivo ectopic bone formation *** modulate WNT signaling,which is essential to maintain skeletal homeostasis,but the specific role of SFRP2 in BMSCs/SSCs is ***,we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and *** skeleton of Sfrp2-def\c\ent(KO)mice is overtly normal;but their BMSCs/SSCs exhibit reduced colony-forming efficiency,reflecting low SSC self-renewal/***2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation ***,regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO ***2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium ***,activation of the Wnt co-receptor;Lrp6,and expression of Wnt target genes,Axin2,C-myc and Cyclin Dl,were reduced in Sfrp2-deficient BMSCs/*** of recombinant Sfrp2 restored most of these activities,suggesting that Sfrp2 acts as a Wnt *** demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone ***2 is also a useful marker of BMSC/SSC multipotency,and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products.

关键词： skeletal impaired healing

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KDM6B epigenetically regulates odontogenic differentiation of dental mesenchymal stem cells

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International Journal of Oral Science 2013年第4期5卷 200-205页

作者： Juan Xu Bo Yu Christine Hong Cun-Yu Wang Department of Stomatology Chinese People's Liberation Army General Hospital Division of Oral biology and Medicine School of DentistryUniversity of California section of Orthodontics School of DentistryUniversity of California Department of Bioengineering Henry Samueli School of Engineering and Applied ScienceUniversity of California

Mesenchymal stem cells （MSCs） have been identified and isolated from dental tissues, including stem cells from apical papilla, which demonstrated the ability to differentiate into dentin-forming odontoblasts. The histone demethylase KDM6B （also known as JMJD3） was shown to play a key role in promoting osteogenic commitment by removing epigenetic marks H3K27me3 from the promoters of osteogenic genes. Whether KDM6B is involved in odontogenic differentiation of dental MSCs, however, is not known. Here, we explored the role of KDM6B in dental MSC fate determination into the odontogenic lineage. Using shRNA-expressing lentivirus, we performed KDM6B knockdown in dental MSCs and observed that KDM6B depletion leads to a significant reduction in alkaline phosphate （ALP） activity and in formation of mineralized nodules assessed by Alizarin Red staining. Additionally, mRNA expression of odontogenic marker gene SP7 （osterix, OSX）, as well as extracellular matrix genes BGLAP （osteoclacin, OCN） and SPP1 （osteopontin, OPN）, was suppressed by KDM6B depletion. When KDM6B was overexpressed in KDM6B-knockdown MSCs, odontogenic differentiation was restored, further confirming the facilitating role of KDM6B in odontogenic commitment. Mechanistically, KDM6B was recruited to bone morphogenic protein 2 （BMP2） promoters and the subsequent removal of silencing H3K27me3 marks led to the activation of this odontogenic master transcription gene. Taken together, our results demonstrated the critical role of a histone demethylase in the epigenetic regulation of odontogenic differentiation of dental MSCs. KDM6B may present as a potential therapeutic target in the regeneration of tooth structures and the repair of craniofacial defects.

关键词： bone morphogenic protein dental mesenchymal stem cell epigenetics KDM6B odontogenic differentiation

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Stem cells, growth factors and scaffolds in craniofacial regenerative medicine

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Genes & Diseases 2016年第1期3卷 56-71页

作者： Viktor Tollemar Zach J.Collier Maryam K.Mohammed Michael J.Lee Guillermo A.Ameer Russell R.Reid The University of Chicago Pritzker School of Medicine ChicagoIL 60637USA Department of Orthopedic Surgery and Rehabilitation Medicine The University of Chicago Medical CenterChicagoIL 60637USA Laboratory of craniofacial biology and Development Section of Plastic and Reconstructive SurgeryDepartment of SurgeryThe University of Chicago MedicineChicagoIL 60637USA Department of Surgery Feinberg School of MedicineChicagoIL 60611USA Biomedical Engineering Department Northwestern UniversityEvanstonIL 60208USA

Current reconstructive approaches to large craniofacial skeletal defects are often complicated and ***-sized defects are unable to heal via natural regenerative processes and require surgical intervention,traditionally involving autologous bone(mainly in the form of nonvascularized grafts)or *** bone grafts remain the gold standard of care in spite of the associated risk of donor site *** engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal *** strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials,osteoblastic stem cells,as well as osteoinductive growth factors and small *** of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone *** properties include osteoconduction,osteoinduction,biocompatibility,biodegradability,vascularization,and progenitor cell *** review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.

关键词： Bone regeneration craniofacial defects Osteogenesis Regenerative medicine Scaffolds Tissue engineering

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Histone methyltransferases and demethylases:regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells

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International Journal of Oral Science 2015年第4期7卷 197-204页

作者： Peng Deng Qian-Ming Chen Christine Hong Cun-Yu Wang Division of Oral biology and Medicine School of DentistryUniversity of California at Los Angeles State Key Laboratory of Oral Disease West China School of StomatologySichuan University section of Orthodontics School of DentistryUniversity of California at Los Angeles Department of Bioengineering Henry Samueli School of Engineering and Applied ScienceUniversity of California at Los Angeles

Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su（var）3-9, enhancer-of-zeste, trithorax （SET） domain-containing family and the Jumonji C （JmjC） domain-containing family represent the major histone lysine methyltransferases （KMTs） and histone lysine demethylases （KDMs）, respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.

关键词： adipogenesis histone methylation histone lysine methyltransferase histone lysine demethylase mesenchymal stemcells osteogenesis

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Transgenic PDGF-BB sericin hydrogel potentiates bone regeneration of BMP9-stimulated mesenchymal stem cells through a crosstalk of the Smad-STAT pathways

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Regenerative Biomaterials 2023年第1期10卷 181-193页

作者： Hui-Jie Zhang Fu-Shu Li Feng Wang Han Wang Tong-Chuan He Russell R.Reid Bai-Cheng He Qingyou Xia Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing Chongqing Medical UniversityChongqing 400016China Department of Pharmacology School of PharmacyChongqing Medical UniversityChongqing 400016China Department of Pharmacy Chongqing Emergency Medical CenterChongqing University Central HospitalChongqing 400014China Biological Science Research Center Chongqing Key Laboratory of Sericultural ScienceChongqing Engineering and Technology Research Center for Novel Silk MaterialsSouthwest UniversityChongqing 400715China Department of Pharmacy Panzhou People’s HospitalGuizhou 553599China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Laboratory of craniofacial biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Silk as a natural biomaterial is considered as a promising bone substitute in tissue *** and fibroin are the main components of silk and display unique features for their programmable mechanical properties,biocompatibility,biodegradability and morphological *** has been reported that sericin recombinant growth factors(GFs)can support cell proliferation and induce stem cell differentiation through cross-talk of signaling pathways during tissue *** transgenic technology allows the productions of bioactive heterologous GFs as fusion proteins with sericin,which are then fabricated into solid matrix or hydrogel ***,using an injectable hydrogel derived from transgenic platelet-derived GF(PDGF)-BB silk sericin,we demonstrated that the PDGF-BB sericin hydrogel effectively augmented osteogenesis induced by bone morphogenetic protein(BMP9)-stimulated mesenchymal stem cells(MSCs)in vivo and in vitro,while inhibiting adipogenic *** gene expression and protein-protein interactions studies demonstrated that BMP9 and PDGF-BB synergistically induced osteogenic differentiation through the cross-talk between Smad and Stat3 pathways in ***,our results provide a novel strategy to encapsulate osteogenic factors and osteoblastic progenitors in transgenic sericin-based hydrogel for robust bone tissue engineering.

关键词： biomaterials growth factor BMP9 osteogenesis

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