{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:44:18Z","timestamp":1760233458506,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H05254","20H00308","20K21087"],"award-info":[{"award-number":["18H05254","20H00308","20K21087"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Malignant melanoma favors spreading to bone, resulting in a weakened bone with a high fracture risk. Here, we revealed the disorganized alignment of apatite crystals in the bone matrix associated with the homing of cancer cells by developing an artificially controlled ex vivo melanoma bone metastasis model. The ex vivo metastasis model reflects the progressive melanoma cell activation in vivo, resulting in decreased bone mineral density and expression of MMP1-positive cells. Moreover, less organized intercellular connections were observed in the neighboring osteoblasts in metastasized bone, indicating the abnormal and randomized organization of bone matrix secreted by disconnected osteoblasts. Our study revealed that the deteriorated microstructure associated with disorganized osteoblast arrangement was a determinant of malignant melanoma-related bone dysfunction.<\/jats:p>","DOI":"10.3390\/biom11020131","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T12:16:18Z","timestamp":1611144978000},"page":"131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impaired Alignment of Bone Matrix Microstructure Associated with Disorganized Osteoblast Arrangement in Malignant Melanoma Metastasis"],"prefix":"10.3390","volume":"11","author":[{"given":"Aira","family":"Matsugaki","sequence":"first","affiliation":[{"name":"Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryota","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan"},{"name":"Teijin Nakashima Medical Co. Ltd., 688-1, Joto-Kitagata, Higashi-ku, Okayama 709-0625, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumihito","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Takehana","sequence":"additional","affiliation":[{"name":"Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8052-1698","authenticated-orcid":false,"given":"Takayoshi","family":"Nakano","sequence":"additional","affiliation":[{"name":"Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1002\/jbmr.3618","article-title":"Understanding the bone in cancer metastasis","volume":"33","author":"Fornetti","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1007\/s11914-018-0480-6","article-title":"Osteoblastic factors in prostate cancer bone metastasis","volume":"16","author":"Lin","year":"2018","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1097\/00008390-200204000-00010","article-title":"Malignant melanoma metastatic to the gastrointestinal tract","volume":"12","author":"Panagiotou","year":"2002","journal-title":"Melanoma Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/jbmr.1825","article-title":"Degree of biological apatite c-axis orientation rather than bone mineral density controls mechanical function in bone regenerated using recombinant bone morphogenetic protein-2","volume":"28","author":"Ishimoto","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.bone.2012.07.003","article-title":"Biological apatite (BAp) crystallographic orientation and texture as a new index for assessing the microstructure and function of bone regenerated by tissue engineering","volume":"51","author":"Nakano","year":"2012","journal-title":"Bone"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/jbm.a.35189","article-title":"Quantitative regulation of bone-mimetic, oriented collagen\/apatite matrix structure depends on the degree of osteoblast alignment on oriented collagen substrates","volume":"103","author":"Matsugaki","year":"2015","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.biomaterials.2014.10.025","article-title":"Abnormal arrangement of a collagen\/apatite extracellular matrix orthogonal to osteoblast alignment is constructed by a nanoscale periodic surface structure","volume":"37","author":"Matsugaki","year":"2015","journal-title":"Biomaterials"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S8756-3282(02)00850-5","article-title":"Unique alignment and texture of biological apatite crystallites in typical calcified tissues analyzed by microbeam x-ray diffractometer system","volume":"31","author":"Nakano","year":"2002","journal-title":"Bone"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1007\/s00774-015-0658-2","article-title":"Evaluation of crystallographic orientation of biological apatite in vertebral cortical bone in ovariectomizedcynomolgus monkeys treated with minodronic acid and alendronate","volume":"34","author":"Tanaka","year":"2016","journal-title":"J. Bone Miner. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.bone.2015.07.015","article-title":"Altered material properties are responsible for bone fragility in rats with chronic kidney injury","volume":"81","author":"Iwasaki","year":"2015","journal-title":"Bone"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41413-020-00105-1","article-title":"Molecular mechanisms and clinical management of cancer bone metastasis","volume":"8","author":"Wang","year":"2020","journal-title":"Bone Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.bone.2017.01.004","article-title":"Disruption of collagen \/ apatite alignment impairs bone mechanical function in osteoblastic metastasis induced by prostate cancer","volume":"97","author":"Sekita","year":"2017","journal-title":"Bone"},{"key":"ref_13","first-page":"1296","article-title":"Invasiveness of cutaneous malignant melanoma is influenced by matrix metalloproteinase 1 gene polymorphism","volume":"61","author":"Ye","year":"2001","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kimura, Y., Matsugaki, A., Sekita, A., and Nakano, T. (2017). Alteration of osteoblast arrangement via direct attack by cancer cells: New insights into bone metastasis. Sci. Rep., 7.","DOI":"10.1038\/srep44824"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Matsugaki, A., Harada, T., Kimura, Y., Sekita, A., and Nakano, T. (2018). Dynamic collision behavior between osteoblasts and tumor cells regulates the disordered arrangement of collagen fiber\/apatite crystals in metastasized bone. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113474"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bourland, J., Fradette, J., and Auger, F.A. (2018). Tissue-engineered 3D melanoma model with blood and lymphatic capillaries for drug development. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31502-6"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.celrep.2014.09.013","article-title":"Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells","volume":"9","author":"Chao","year":"2014","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fukuda, K., Sugihara, E., Ohta, S., Izuhara, K., Funakoshi, T., Amagai, M., and Saya, H. (2015). Periostin is a key niche component for wound metastasis of melanoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129704"},{"key":"ref_19","first-page":"507","article-title":"Osteoclast Signal Transduction during Bone Metastasis Formation","volume":"19","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.cmet.2015.11.008","article-title":"Metastasis and oxidative stress: Are antioxidants a metabolic driver of progression?","volume":"22","author":"Sotgia","year":"2015","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Matsugaki, A., Matsumoto, S., and Nakano, T. (2020). A novel role of interleukin-6 as a regulatory factor of inflammation-associated deterioration in osteoblast arrangement. IJMS, 21.","DOI":"10.3390\/ijms21186659"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.actbio.2008.07.014","article-title":"Effect of spatial design and thermal oxidation on apatite formation on Ti-15Zr-4Ta-4Nb alloy","volume":"5","author":"Sugino","year":"2009","journal-title":"Acta Biomater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7327","DOI":"10.1016\/j.biomaterials.2012.06.022","article-title":"The alignment of MC3T3-E1 osteoblasts on steps of slip traces introduced by dislocation motion","volume":"33","author":"Matsugaki","year":"2012","journal-title":"Biomaterials"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.bone.2017.06.023","article-title":"Co-deteriorations of anisotropic extracellular matrix arrangement and intrinsic mechanical property in c-src deficient osteopetrotic mouse femur","volume":"103","author":"Ishimoto","year":"2017","journal-title":"Bone"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00223-018-0508-z","article-title":"Osteoporosis changes collagen \/apatite orientation and Young\u2019s modulus in vertebral cortical bone of rat","volume":"104","author":"Ozasa","year":"2019","journal-title":"Calcif. Tissue Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.bone.2012.11.005","article-title":"Design and optimization of the oriented groove on the hip implant surface to promote bone microstructure integrity","volume":"52","author":"Noyama","year":"2013","journal-title":"Bone"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.2320\/matertrans.M2016341","article-title":"Disruption of collagen matrix alignment in osteolytic bone metastasis induced by breast cancer","volume":"57","author":"Sekita","year":"2016","journal-title":"Mater. Trans."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.18063\/ijb.v6i4.293","article-title":"3D printing of anisotropic bone-mimetic structure with controlled fluid flow stimuli for osteocytes: Flow orientation determines the elongation of dendrites","volume":"6","author":"Matsugaki","year":"2020","journal-title":"Int. J. Bioprint."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/jbm.a.36238","article-title":"Construction of human induced pluripotent stem cell-derived oriented bone matrix microstructure by using in vitro engineered anisotropic culture model","volume":"106","author":"Ozasa","year":"2017","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.biomaterials.2019.04.016","article-title":"Unique arrangement of bone matrix orthogonal to osteoblast alignment controlled by Tspan11-mediated focal adhesion assembly","volume":"209","author":"Nakanishi","year":"2019","journal-title":"Biomaterials"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s10555-019-09811-7","article-title":"Cell surface\u2013anchored serine proteases in cancer progression and metastasis","volume":"38","author":"Martin","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.biopha.2016.12.021","article-title":"Role of protease and protease inhibitors in cancer pathogenesis and treatment","volume":"86","author":"Eatemadi","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jsb.2016.12.003","article-title":"Synchronous disruption of anisotropic arrangement of the osteocyte network and collagen\/apatite in melanoma bone metastasis","volume":"197","author":"Sekita","year":"2017","journal-title":"J. Struct. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1091\/mbc.e10-07-0571","article-title":"Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling","volume":"22","author":"Watkins","year":"2011","journal-title":"Mol. Biol. 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