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Open Access | 10.1172/JCI170369
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
2Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, United States of America
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America
4Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
5Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
6Department of Medicine, Bone and Mineral Unit, Oregon Health & Science University, Portland, United States of America
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Published June 17, 2024 - More info
Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes in addition to bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in IFITM5. Here, we generated a conditional Rosa26 knock-in mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in OI type V patients. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with increase in the skeletal progenitor population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 showed decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupts early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.