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The WNT1^(G177C) mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV

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Bone Research 2021年第4期9卷 593-605页

作者： Nele Vollersen Wenbo Zhao Tim Rolvien Fabiola Lange Felix Nikolai Schmidt Stephan Sonntag Doron Shmerling Simon von Kroge Kilian Elia Stockhausen Ahmed Sharaf michaela Schweizer Meliha Karsak Bjorn Busse Ernesto Bockamp Oliver Semler michael amling Ralf Oheim Thorsten Schinke Timur Alexander Yorgan Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany PolyGene AG 8153 RumlangSwitzerland ETH Phenomics Center(EPIC) ETH Zurich8092 ZurichSwitzerland Neuronal and Cellular Signal Transduction Center for Molecular Neurobiology Hamburg(ZMNH)University Medical Center Hamburg-Eppendorf20246 HamburgGermany Center for Molecular Neurobiology Hamburg(ZMNH) University Medical CenterHamburg-Eppendorf20246 HamburgGermany Institute for Translational Immunology and Research Center for Immunotherapy University Medical CenterJohannes Gutenberg UniversityD 55131 MainzGermany Faculty of Medicine and University Hospital Cologne Department of PediatricsUniversity of Cologne50937 CologneGermany

The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV(OI-XV)has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming *** such aninfluence was supported by subsequent studies,a mouse model of OI-XV remained to be ***,we introduced a previously identified disease-causing mutation(G177C)into the murine Wnt1 *** Wnt1^(G177C/G177C)mice were viable and did not display defects in brain development,but the majority of 24-week-old Wnt1^(G177C/G177C)mice had skeletal *** increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix ***,the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5,the latter mimicking the effect of sclerostin ***,transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix *** together,our data demonstrate that regulating bone matrix quality is a primary function of *** further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.

关键词： WNT1 skeletal impaired

Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF–RANKL signaling

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Bone Research 2018年第1期6卷 50-59页

作者： Alexander Bartelt Friederike Behler-Janbeck F.Timo Beil Till Koehne Brigitte Müller Tobias Schmidt Markus Heine Laura Ochs Tayfun Yilmaz Martin Dietrich Jan P.Tuckermann michael amling Joachim Herz Thorsten Schinke Joerg Heeren Andreas Niemeier Department of Orthopaedics University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Biochemistry and Molecular Cell Biology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Osteology and Biomechanics University Medical Center Hamburg-EppendorfMartinistr5220246 HamburgGermany Department of Orthodontics University Medical Center Hamburg-EppendorfMartinistr52 20246 HamburgGermany Department of Anatomy and Experimental Morphology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Molecular Genetics University of Texas Southwestern Medical CenterDallasTX 75390USA Institute for Comparative Molecular Endocrinology University of UlmUlmGermany Correspondence:Andreas Niemeier Department of Genetics and Complex Diseases&Sabriülker Center Harvard T.H.Chan School of Public Health665 Huntington AvenueBostonMA 02115USA

Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1(Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone *** lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand(RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor(PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF–RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans.

关键词： PDGFRβ RANKL activator receptor imatinib axis gene vivo

Procalcitonin is expressed in osteoblasts and limits bone resorption through inhibition of macrophage migration during intermittent PTH treatment

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Bone Research 2022年第1期10卷 107-121页

作者： Anke Baranowsky Denise Jahn Shan Jiang Timur Yorgan Peter Ludewig Jessika Appelt Kai K.Albrecht Ellen Otto Paul Knapstein Antonia Donat Jack Winneberger Lana Rosenthal Paul Köhli Cordula Erdmann Melanie Fuchs Karl-Heinz Frosch Serafeim Tsitsilonis michael amling Thorsten Schinke Johannes Keller Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-EppendorfHamburg 20246Germany Department of Osteology and Biomechanics University Medical Center Hamburg-EppendorfHamburg 20246Germany Center for Musculoskeletal Surgery Charité-Universitätsmedizin BerlinBerlin 13353Germany Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration Charité-Universitätsmedizin BerlinBerlin 13353Germany Department of Neurology University Medical Center Hamburg-EppendorfHamburg 20251Germany Berlin Institute of Health Berlin 10178Germany

Intermittent injections of parathyroid hormone(iPTH) are applied clinically to stimulate bone formation by osteoblasts, although continuous elevation of parathyroid hormone(PTH) primarily results in increased bone resorption. Here, we identified Calca,encoding the sepsis biomarker procalcitonin(ProCT), as a novel target gene of PTH in murine osteoblasts that inhibits osteoclast formation. During iPTH treatment, mice lacking ProCT develop increased bone resorption with excessive osteoclast formation in both the long bones and axial skeleton. Mechanistically, ProCT inhibits the expression of key mediators involved in the recruitment of macrophages, representing osteoclast precursors. Accordingly, ProCT arrests macrophage migration and causes inhibition of early but not late osteoclastogenesis. In conclusion, our results reveal a potential role of osteoblast-derived ProCT in the bone microenvironment that is required to limit bone resorption during iPTH.

关键词： treatment representing skeleton

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： Laura J.Brylka Assil-Ramin Alimy Miriam E.A.Tschaffon-Müller Shan Jiang Tobias Malte Ballhause Anke Baranowsky Simon von Kroge Julian Delsmann Eva Pawlus Kian Eghbalian Klaus Püschel Astrid Schoppa Melanie Haffner-Luntzer David J.Beech Frank Timo Beil michael amling Johannes Keller Anita Ignatius Timur A.Yorgan Tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal Medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and Metabolic Medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell *** we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in *** we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)*** with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate ***,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth *** skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of ***,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage ***,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) *** further observed increased Piezo1 protein abundance in cartilaginous zones of human ***,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in ***,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

Practice patterns and outcomes of equivocal bone scans for patients with castration-resistant prostate cancer: Results from SEARCH

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Asian Journal of Urology 2019年第3期6卷 242-248页

作者： Brian T.Hanyok Mary M.Everist Lauren E.Howard Amanda M.De Hoedt William J.Aronson Matthew R.Cooperberg Christopher J.Kane Christopher L.amling Martha K.Terris Stephen J.Freedland Urology Section Department of SurgeryVeterans Affairs Medical CenterDurhamNCUSA New York Medical College ValhallaNYUSA Department of Biostatistics and Bioinformatics Duke University School of MedicineDurhamNCUSA Urology Section Department of SurgeryVeterans Affairs Medical CenterGreater Los AngelesLos AngelesCAUSA Department of Urology University of California at Los Angeles Medical CenterLos AngelesCAUSA Departments ofUrology and Epidemiology&Biostatistics University of CaliforniaSan FranciscoCAUSA Urology Section Department of SurgeryVeterans Affairs Medical CenterSan FranciscoCAUSA Division of Urology Department of SurgeryUniversity of California at San Diego Medical CenterSan DiegoCAUSA Division of Urology Department of SurgeryOregon Health&Science UniversityPortlandORUSA Urology Section Division of SurgeryVeterans Affairs Medical CenterAugustaGAUSA Division of Urologic Surgery Department of SurgeryMedical College of GeorgiaAugustaGAUSA Division of Urology Department of SurgerySamuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCAUSA Center for Integrated Research in Cancer and Lifestyle Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCAUSA

Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-up ***:We identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis,of whom 99(15%)had equivocal *** with equivocal scans were segregated into“high-risk”and“low-risk”subcategories based upon wording in the bone scan *** follow-up imaging(bone scans,computed tomography[CT],magnetic resonance imaging[MRI],and X-rays)in the 3 months after the equivocal scan were *** were compared between patients with a positive *** follow-up imaging after an equivocal bone ***:Of 99 men with an equivocal bone scan,43(43%)received at least one follow-up imaging test,including 32/82(39%)with low-risk scans and 11/17(65%)with high-risk scans(p=0.052).Of follow-up tests,67%were negative,14%were equivocal,and 19%were *** those who underwent follow-up imaging,3/32(9%)low-risk men had metastases vs.5/11(45%)high-risk men(p=0.015).Conclusion:While 19%of all men who received follow-up imaging had positive follow-up imaging,only 9%of those with a low-risk equivocal bone scan had metastases versus 45%of those with *** preliminary findings,if confirmed in larger studies,suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging.

关键词： Castration-resistant prostate cancer Equivocal test result Bone scan Radiology report Follow-up imaging Neoplasm metastasis

凋落:Bcl-2是程序性细胞死亡的关键蛋白

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维普期刊数据库

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德国医学 1996年第1期13卷 58-60页

作者： M.amling M.Psl I.Bsler G.Delling 阮幼冰 Hamburger Knochentumor-Register Abteilung OsteopathologiePathologisehes InstitutUniversitt HamburgGermany 同济医科大学

凋落是一种程序性细胞死亡,一种有规律的细胞死亡形式,有别于激发性细胞死亡。程序性细胞死亡的细胞具如下特征:细胞皱缩、染色质凝聚、细胞膜呈典型的外突。在 DNA 水平上,通过 Mg2+/Ca2+相关的核酸内切酶,裂解为180个碱基对大小的若... 详细信息

凋落是一种程序性细胞死亡,一种有规律的细胞死亡形式,有别于激发性细胞死亡。程序性细胞死亡的细胞具如下特征:细胞皱缩、染色质凝聚、细胞膜呈典型的外突。在 DNA 水平上,通过 Mg2+/Ca2+相关的核酸内切酶,裂解为180个碱基对大小的若干片断。在无胞浆成分溢出的情况下。

关键词：凋落程序细胞死亡 Bcl-2

骨膜骨肉瘤组织学特征、标本制作技术、生长模式和鉴别诊断

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德国医学 1996年第4期13卷 234-236页

作者： G.Delling M.amling M.Psl H.Ritzel R.Maas K.Winkler U.Heise M.Werner 武忠弼 Abteilung Osteopathologie Pathologisches InstitutUniversitt HamburgMartinistr.52D-20246 HamburgGermany 同济医科大学

恶性骨肿瘤属于较罕见的肿瘤,其中骨肉瘤还是最常见者。随着认识的不断增加,对几乎所有的骨肿瘤都进行了亚分类,然而将骨肉瘤分为中央性和近皮质骨肉瘤当今原则上仍然是有效的,但这只是一个较粗略的大分类。

关键词：骨膜肿瘤骨膜骨肉瘤病理学诊断