Joan Carol Marini, Ph.D.,M.D.
Section on Heritable Disorders of Bone and Extracellular Matrix
NIHBC 49 - Conte 5A52
Genetic Disorders of Bone and Extracellular Matrix
In an integrated program of laboratory and clinical investigation, the Bone and Extracellular Matrix Branch (BEMB) studies the molecular biology of the heritable connective tissue disorders osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS). Our objective is to elucidate the mechanisms by which the primary gene defect causes skeletal fragility and other connective-tissue symptoms and then apply this knowledge to the treatment of children with these conditions. Recently, we identified the long-sought cause of recessive OI. Discoveries of defects in collagen modification generated a new paradigm for collagen-related disorders of matrix. We have established that structural defects in collagen cause dominant OI while defects in the components of a complex in the endoplasmic reticulum that modifies collagen cause recessive OI. Our challenge now is to understand the cellular and biochemical mechanisms of recessive OI. We also generated a knockin murine model for OI with a classical collagen mutation and are using the model to study disease pathogenesis and the skeletal matrix of OI, the effects of pharmacological therapies, and approaches to gene therapy. Our clinical studies involve children with types II and IV OI, who form a longitudinal study group enrolled in age-appropriate clinical protocols for the treatment of their condition.
Joan Marini, M.D., Ph.D., is Chief of the Bone and Extracellular Matrix Branch, NICHD. She leads the NICHD Osteogenesis Imperfecta research program, in which clinical and bench research are fully integrated. Her lab generated the Brtl mouse model for type IV OI and has played a leading role in the Consortium for OI mutations. In the last five years, her group has been a leader in the exciting new developments about recessive OI, which have revealed important novel findings on the role of collagen prolyl 3-hydroxylation in bone formation. Her clinical research focuses on children with osteogenesis imperfecta and treatment with bisphosphonates and growth hormone.
Dr. Marini received her M.D and Ph.D. in the Medical Scientist Training Program at the Johns Hopkins University School of Medicine. She completed training in pediatrics at Johns Hopkins and Georgetown University Hospital. She did Clinical Genetics specialty training at the NIH InterInstitute Genetics Program. She has twice been awarded the NIH Director’s Award for her work on osteogenesis imperfecta.
Fratzl-Zelman N, Roschger P, Kang H, Jha S, Roschger A, Blouin S, Deng Z, Cabral WA, Ivovic A, Katz J, Siegel RM, Klaushofer K, Fratzl P, Bhattacharyya T, Marini JC. Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction. J Bone Miner Res. 2019;34(5):883-895.
Kang H, Jha S, Ivovic A, Fratzl-Zelman N, Deng Z, Mitra A, Cabral WA, Hanson EP, Lange E, Cowen EW, Katz J, Roschger P, Klaushofer K, Dale RK, Siegel RM, Bhattacharyya T, Marini JC. Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway. J Exp Med. 2020;217(5).
Barnes AM, Ashok A, Makareeva EN, Brusel M, Cabral WA, Weis M, Moali C, Bettler E, Eyre DR, Cassella JP, Leikin S, Hulmes DJS, Kessler E, Marini JC. COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing. Biochim Biophys Acta Mol Basis Dis. 2019;1865(9):2210-2223.
Cabral WA, Fratzl-Zelman N, Weis M, Perosky JE, Alimasa A, Harris R, Kang H, Makareeva E, Barnes AM, Roschger P, Leikin S, Klaushofer K, Forlino A, Backlund PS, Eyre DR, Kozloff KM, Marini JC. Substitution of murine type I collagen A1 3-hydroxylation site alters matrix structure but does not recapitulate osteogenesis imperfecta bone dysplasia. Matrix Biol. 2020;90:20-39.
Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis Imperfecta: Mechanisms and signaling pathways connecting classical and rare OI types. Endocr Rev. 2021.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on July 12th, 2017