{"created":"2023-06-20T13:23:17.861342+00:00","id":4086,"links":{},"metadata":{"_buckets":{"deposit":"5da34931-8f89-4b8d-83b0-4a3d2de9f9a4"},"_deposit":{"created_by":21,"id":"4086","owners":[21],"pid":{"revision_id":0,"type":"depid","value":"4086"},"status":"published"},"_oai":{"id":"oai:ir.soken.ac.jp:00004086","sets":["2:430:20"]},"author_link":["2299","2300","2298"],"item_1_creator_2":{"attribute_name":"著者名","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"片岡, 太郎"}],"nameIdentifiers":[{}]}]},"item_1_creator_3":{"attribute_name":"フリガナ","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"カタオカ, タロウ"}],"nameIdentifiers":[{}]}]},"item_1_date_granted_11":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2013-03-22"}]},"item_1_degree_grantor_5":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_name":"総合研究大学院大学"}]}]},"item_1_degree_name_6":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士（理学）"}]},"item_1_description_12":{"attribute_name":"要旨","attribute_value_mlt":[{"subitem_description":"Bones have crucial roles in supporting body as one of the locomotor\napparatuses, maintaining mineral homeostasis and protecting vital organs.\nBone tissues are classified into two types by visual appearance and location,\n“cancellous (trabecular) bone” and “cortical bone”. Cancellous bone, also\nknown as sponge bone, is found in vertebral body and both ends of long bone\nlike tibia and femur. It has larger surface area but shows weaker strength\nthan cortical bone. It provides structural strength to bone tissue. Cortical\nbone forms cortex of most bones. It is stronger and stiffer than cancellous\nbone. The outer shell surrounding the cancellous bone at the end of the joints\nis also made up of cortical bone.\nBones in adulthood are continuously renewed by old bone resorption by\nosteoclasts and new bone formation by osteoblasts. This process is called\n“bone remodeling”. Bone remodeling is important for bone homeostasis, and is\nessential for maintenance of healthy bones. Disruption of ideal balance in\nbone remodeling causes abnormal bone mass such as osteoporosis and\nosteopetrosis. A series of longitudinal studies of human populations have\nshowed that bone mineral density (BMD) is correlated with physical strength\nof bone, and a most important risk factor for bone fracture.\nHowever, human studies also indicated that BMD at any time points is well\ncorrelated with peak (highest) bone mass in the early growth phase of bone.\nFurthermore, these studies have also revealed that more than half of\nvariation in the early growth phase of bone, which occurs over a short time\nperiod during puberty, is determined predominantly by genetic factors.\nRecent advance in X-ray micro-computed tomography (micro-CT) has\nenabled to analyze three-dimensional (3D) structure of the cancellous bones\nwithout tissue destruction. Such studies have indicated that the risk of bone\nfracture in human elders increases as BMD decreases, but the biomechanical\ncompetence (physical strength) of bone and risk factor of bone fracture are\ndependent not only on BMD as the absolute amount of bone mass, but also on\nthe 3D microstructure of cancellous bone. This fact suggests that we need to\npay more attention to bone microstructure for identifying genetic risk factors\nfor bone fracture. Recent studies also showed that there is a very good\ncorrelation between the bone microstructural measure obtained from the\nX-ray micro-CT and that obtained from conventional histological 2D sections.\nIn particular, excellent correlation was found between bone volume fraction\n(BV/TV), which is the measure of cancellous bone volume per total volume\nsurrounded by cortical bone, and the data of the histological 2D sections.\nSubsequent studies of microstructure of mouse cancellous bone by X-ray\nmicro-CT have also showed that cancellous bone loss is observed even in the\nearly growth phase of bone, and occurs continuously until the later adulthood\nstage, consistent with facts that cancellous bone is highly sensitive to change\nof bone metabolism, and is easily fractured in human elders.\nForward genetics approaches to explore polygenic factors responsible for bone\nhomeostasis can be efficiently pursued in animal models. Usage of the animal\nmodels enables to control genome heterogeneity and environmental factors,\nand improves the power to identify heritable regulation of bone homeostasis.\nVariations in genome sequences and bone phenotypes among different inbred\nstrains of mice are amenable to genetic analyses of polygenic complex traits of\nbone phenotypes via the quantitative trait loci (QTL) analysis. In fact, several\nstudies with inbred mouse strains have revealed QTLs that affect\nmicrostructure of mouse cancellous bone. However, none of causative genes\nfor the QTLs has been identified so far.\nIn this study, I focused on genetic factors responsible for variation in\nmicrostructure of mouse cancellous bone at the earlier growth phase of 6 to 10\nweeks of age, because the early growth phase is critical for bone density and\nmicrostructure at any time in the later adulthood stage. The genes that\nregulate bone formation during embryonic development have been intensively\nstudied by reverse genetics approaches with knockout mouse strains, and the\ngenes involved in bone homeostasis at the later adulthood stage have been\nextensively studied by genome wide association study for human populations.\nBy contrast, there is only limited information for genes acting for forming\nbone microstructure at the earlier and growing phase of bone. This is another\nreason that I focused on the early growth phase of mouse bone. For genetic\nanalyses in this study, I used two strains, a laboratory inbred strain C57BL/6J\n(hereafter abbreviated B6) and Japanese wild mouse (Mus musculus\nmolossinus)-derived MSM/Ms.\nThese two strains are genetically very distant one another, and more than ten\nmillion SNPs have been identified between these two strains, and the SNP\ndata are now fully available. As a consequence of its genome divergence from\nB6 and other laboratory strains, MSM/Ms appeared to have unique complex\ntraits that are never observed in standard laboratory strains. Another great\nadvantage to use the B6 and MSM/Ms strains is that a full set of consomic\nstrains, in which every B6 chromosome is replaced by counterpart of\nMSM/Ms, is now established and available for exploring QTLs.\nAt the beginning of this study, the X-ray micro-CT phenotyping of\nmicrostructure of cancellous bone of tibia at 10 weeks of age showed that\nMSM/Ms has far smaller value of bone volume fraction (BV/TV) than that of\nB6. This finding prompted me to pursue systematic phenotype screening of\nthe same trait for the full set of B6-MSM/Ms consomic strains. As a result, I\nfound that among all consomic strains B6-Chr15MSM carrying MSM/Ms-derive\nchromosome 15 (Chr15) shows the smallest cancellous bone volume fraction,\nindicating that mouse Chr15 harbors QTLs affecting bone microstructure,\nwhich is likely relevant to bone physical strength. Next, in order to further\ndissect genetic factors into sub-regions of Chr15, I generated nested\nsub-consomic strains that harbor sub-divided fragments of MSM/Ms Chr15.\nBone phenotyping of these strains revealed that at least four chromosomal\nblocks of Chr15 genetically control the trait of cancellous bone microstructure.\nI named these blocks, Block 1 to 4, each of which contains at least one QTL\naffecting microstructure of cancellous bone. None of these four QTLs has been\nreported by other groups’ previous studies.\nIt is of interest to note that the MSM/Ms alleles at the QTLs in the Block 2, 3\nand 4 decrease the bone volume fraction (BV/TV) relative to B6 as were\nexpected, but the MSM/Ms allele at the QTL in Block 1 rather increases the\nBV/TV value relative to B6. Thus, the analysis with the sub-consomic strains\nrevealed marked complexity of genetic architecture to control cancellous bone\nmicrostructure in mouse, and demonstrated that the analysis with consomic\nand sub-consomic strains has strong power to detect each of numerous QTLs,\neven if its phenotypic effect is modest.\nFinally, I paid special attention to one short sub-block, named Sub-block 1-1,\nincluded in Block 1, the borders of which are defined by difference in the\nMSM/Ms-derived fragments of two sub-consomic strains. I intensively\nexplored candidates of the causative gene for the QTL in Sub-block 1-1,\nbecause no known gene to be involved in bone regulation and homeostasis is\nassigned to this interval. I identified eight genes as candidates. In particular,\nfour of them, Ankrd33b, Ropn1l, March6 and Fam173b, are good candidates\nfrom the aspects of expression pattern difference and amino acid change\nbetween B6 and MSM/Ms. Thus, this study provides indispensable clues for\nunderstanding genetic architecture underlying bone regulation and\nhomeostasis of mouse, and for searching genetic factors responsible for\nosteoporosis in human.","subitem_description_type":"Other"}]},"item_1_description_18":{"attribute_name":"フォーマット","attribute_value_mlt":[{"subitem_description":"application/pdf","subitem_description_type":"Other"}]},"item_1_description_7":{"attribute_name":"学位記番号","attribute_value_mlt":[{"subitem_description":"総研大甲第1606号 ","subitem_description_type":"Other"}]},"item_1_select_14":{"attribute_name":"所蔵","attribute_value_mlt":[{"subitem_select_item":"有"}]},"item_1_select_8":{"attribute_name":"研究科","attribute_value_mlt":[{"subitem_select_item":"生命科学研究科"}]},"item_1_select_9":{"attribute_name":"専攻","attribute_value_mlt":[{"subitem_select_item":"18 遺伝学専攻"}]},"item_1_text_10":{"attribute_name":"学位授与年度","attribute_value_mlt":[{"subitem_text_value":"2012"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"KATAOKA, Taro","creatorNameLang":"en"}],"nameIdentifiers":[{}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2016-02-26"}],"displaytype":"simple","filename":"甲1606_要旨.pdf","filesize":[{"value":"359.8 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"要旨・審査要旨","url":"https://ir.soken.ac.jp/record/4086/files/甲1606_要旨.pdf"},"version_id":"c73f4dad-79fe-456d-8734-6045894bb7ea"},{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2016-02-17"}],"displaytype":"simple","filename":"甲1606_本文.pdf","filesize":[{"value":"1.7 MB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"本文","url":"https://ir.soken.ac.jp/record/4086/files/甲1606_本文.pdf"},"version_id":"3d18e9c7-683c-4ac8-91da-abf0a27cf310"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"thesis","resourceuri":"http://purl.org/coar/resource_type/c_46ec"}]},"item_title":"Exploration of genetic factors controlling cancellous bone microstructure of mouse","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Exploration of genetic factors controlling cancellous bone microstructure of mouse"},{"subitem_title":"Exploration of genetic factors controlling cancellous bone microstructure of mouse","subitem_title_language":"en"}]},"item_type_id":"1","owner":"21","path":["20"],"pubdate":{"attribute_name":"公開日","attribute_value":"2013-11-21"},"publish_date":"2013-11-21","publish_status":"0","recid":"4086","relation_version_is_last":true,"title":["Exploration of genetic factors controlling cancellous bone microstructure of mouse"],"weko_creator_id":"21","weko_shared_id":21},"updated":"2023-06-20T15:14:47.125066+00:00"}