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Four mouse models of severe joint OA<\/jats:styled-content> were generated: cartilage\u2010specific Egfr<\/jats:italic>\u2013knockout (Egfr<\/jats:italic>\u2010CKO<\/jats:styled-content>) mice at 2 months after surgical destabilization of the medial meniscus (DMM<\/jats:styled-content>), Egfr<\/jats:italic>\u2010CKO<\/jats:styled-content> mice with aging\u2010related spontaneous OA<\/jats:styled-content>, wild\u2010type (WT<\/jats:styled-content>) mice at 10 months after DMM<\/jats:styled-content>, and WT<\/jats:styled-content> mice at 14 weeks after DMM<\/jats:styled-content> plus hemisectomy of the meniscus (DMMH<\/jats:styled-content>) surgery. As an additional model, mice with knockout of the sclerostin gene (Sost<\/jats:italic>\u2010KO<\/jats:styled-content>) were subjected to DMMH<\/jats:styled-content> surgery. Knee joints were examined by micro\u2010CT<\/jats:styled-content>, histology, and immunohistochemical analyses.<\/jats:p><\/jats:sec>Results<\/jats:title>Examination of the mouse distal femur by 3\u2010D micro\u2010CT<\/jats:styled-content> revealed a positive correlation between SBP<\/jats:styled-content> thickness and the loading status in normal knees. In all 4 mouse models of late\u2010stage OA<\/jats:styled-content>, SBP<\/jats:styled-content> sclerosis was restricted to the areas under severely eroded articular cartilage. This was accompanied by elevated bone formation at the bone marrow side of the SBP<\/jats:styled-content> and a drastic reduction in the levels of sclerostin in osteocytes within the SBP<\/jats:styled-content>. Unlike in WT<\/jats:styled-content> mice, no further increase in the thickness of the SBP<\/jats:styled-content> was observed in response to DMMH<\/jats:styled-content> in Sost<\/jats:italic>\u2010KO<\/jats:styled-content> mice.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Since focal stress on the SBP<\/jats:styled-content> underlying sites of cartilage damage increases during late stages of OA<\/jats:styled-content>, these findings establish mechanical loading\u2013induced attenuation of sclerostin expression and elevation of bone formation along the SBP<\/jats:styled-content> surface as the major mechanisms characterizing subchondral bone phenotypes associated with severe late\u2010stage OA<\/jats:styled-content> in mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40351","type":"journal-article","created":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T14:36:40Z","timestamp":1507819000000},"page":"230-241","source":"Crossref","is-referenced-by-count":67,"title":["Loading\u2010Induced Reduction in Sclerostin as a Mechanism of Subchondral Bone Plate\u00a0Sclerosis in Mouse Knee Joints During Late\u2010Stage Osteoarthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Haoruo","family":"Jia","sequence":"first","affiliation":[{"name":"University of Pennsylvania, Philadelphia and The First Affiliated Hospital of the Medical College Shihezi University Shihezi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Shandong University Qilu Hospital, Jinan, China and University of Pennsylvania Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Wei","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia and Union Hospital Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tong","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia and Union Hospital Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Tower","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia and Union Hospital Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Chandra","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia and Union Hospital Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong University Qilu Hospital, Jinan, China and University of Pennsylvania Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyang","family":"Sun","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia and Union Hospital Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaochun","family":"Yang","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Badar","sequence":"additional","affiliation":[{"name":"Oakland University Rochester Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kairui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanfang Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Ju","family":"Tseng","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia and Union Hospital Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Kramer","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Kneissel","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xia","sequence":"additional","affiliation":[{"name":"Oakland University Rochester Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. 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