{"title":"Involvement of Heat Shock Protein 47 in Osteophyte Formation of Knee Joint Osteoarthritis","authors":"Yuta Otsuka , Arepati Adili , Masahiro Momoeda , Yoshifumi Negishi , Haruka Kaneko , Chiho Yoshinaga , Yuka Kenzaki , Takako Negishi-Koga , Muneaki Ishijima , Yasunori Okada","doi":"10.1016/j.ajpath.2025.03.003","DOIUrl":null,"url":null,"abstract":"<div><div>Osteophytes contribute to the development and progression of knee osteoarthritis (OA). Although transforming growth factor-β (TGF-β) and bone morphogenic protein-2 (BMP2) are known to induce osteophytes, regulators of osteophyte formation remain elusive. This study aimed to search for molecules that modulate osteophytosis in a mouse knee OA model. Proteomic analysis, followed by immunohistochemistry of osteophyte and articular cartilage, identified heat shock protein 47 (HSP47), a molecular chaperone for procollagens, as a molecule selectively overexpressed by osteophyte fibrocartilaginous cells. The treatment of TGF-β3 and BMP2 to a three-dimensional pellet culture of mouse mesenchymal stem cells caused their differentiation into osteophyte-like cells accompanied with the up-regulation of HSP47. The pellet sizes of stimulated three-dimensional–cultured mesenchymal stem cells were significantly reduced by knockdown of HSP47 or treatment with AK778 (HSP47 inhibitor), because of increased apoptosis. Furthermore, intra-articular AK778 injections suppressed osteophyte formation in a mouse OA model. Importantly, the studies with human samples demonstrated HSP47 overexpression by osteophyte fibrocartilaginous cells in human OA knee joints. Similarly, the overexpression of HSP47 was observed in the TGF-β3– and BMP2-treated human osteophytic cell spheroids as well as the size reduction of spheroids by AK778 treatment. These findings highlight the promoting function of HSP47 in osteophyte formation in OA knee joints and suggest that therapeutic interventions targeting HSP47 may be of clinical value.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1279-1293"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S000294402500104X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Osteophytes contribute to the development and progression of knee osteoarthritis (OA). Although transforming growth factor-β (TGF-β) and bone morphogenic protein-2 (BMP2) are known to induce osteophytes, regulators of osteophyte formation remain elusive. This study aimed to search for molecules that modulate osteophytosis in a mouse knee OA model. Proteomic analysis, followed by immunohistochemistry of osteophyte and articular cartilage, identified heat shock protein 47 (HSP47), a molecular chaperone for procollagens, as a molecule selectively overexpressed by osteophyte fibrocartilaginous cells. The treatment of TGF-β3 and BMP2 to a three-dimensional pellet culture of mouse mesenchymal stem cells caused their differentiation into osteophyte-like cells accompanied with the up-regulation of HSP47. The pellet sizes of stimulated three-dimensional–cultured mesenchymal stem cells were significantly reduced by knockdown of HSP47 or treatment with AK778 (HSP47 inhibitor), because of increased apoptosis. Furthermore, intra-articular AK778 injections suppressed osteophyte formation in a mouse OA model. Importantly, the studies with human samples demonstrated HSP47 overexpression by osteophyte fibrocartilaginous cells in human OA knee joints. Similarly, the overexpression of HSP47 was observed in the TGF-β3– and BMP2-treated human osteophytic cell spheroids as well as the size reduction of spheroids by AK778 treatment. These findings highlight the promoting function of HSP47 in osteophyte formation in OA knee joints and suggest that therapeutic interventions targeting HSP47 may be of clinical value.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.