한빛사논문
- 조회1,310
Heeseog Kang1*, Smita Jha2,3*, Aleksandra Ivovic4*, Nadja Fratzl-Zelman5, Zuoming Deng6, Apratim Mitra7, Wayne A. Cabral1, Eric P. Hanson8, Eileen Lange9, Edward W. Cowen10, James Katz9, Paul Roschger5, Klaus Klaushofer5, Ryan K. Dale7, Richard M. Siegel4**, Timothy Bhattacharyya11**, and Joan C. Marini1**
1Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD;
2Clinical and Investigative Orthopedics Surgery Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
3Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD;
4Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
5Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse, and Allgemeine Unfallversicherungsanstalt Trauma Center Meidling, First Medical Department Hanusch Hospital, Vienna, Austria;
6Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
7Bioinformatics and Scientific Programming Core, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD;
8Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
9Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
10Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD;
11Section on Congenital Disorders, Clinical Center, National Institutes of Health, Bethesda, MD.
*H. Kang, S. Jha, and A. Ivovic contributed equally to this paper;
**R.M. Siegel, T. Bhattacharyya, and J.C. Marini contributed equally to this paper;
Correspondence to Joan C. Marini
Abstract
Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical “dripping candle wax” melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation–positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-β/SMAD3 activation by BMP signaling in SMAD3 mutation–positive endosteal melorheostosis, which may guide future therapies.
논문정보
- Research article
- 2020년 03월 (BRIC 등록일 2020-04-01)
- 국외 연구진
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
