title: Bone marrow fibrosis with fibrocytic and immunoregulatory responses induced by β-catenin activation in osteoprogenitors.
abstract: Wnt/β-catenin signaling has been reported to contribute to the development of bone fibrous dysplasia. However, it remains unclear whether fibrocytes and immune cells are involved in this β-catenin-mediated bone marrow fibrosis. In this study, we showed that constitutive activation of β-catenin by Col1a1-Cre (3.6-kb) exhibited bone marrow fibrosis, featured with expanded populations of fibrocytes, myofibroblasts and osteoprogenitors. Lineage tracing and IHC examinations showed that Col3.6-Cre display Cre recombinase activity not only in osteoprogenitors, but also in monocyte-derived fibrocytes in the endosteal niches of bones. Additionally, β-catenin stimulated the secretion of cytokines and pro-fibrotic signals in bone marrow, including GM-CSF, TGFβ1 and VEGF. Consequently, the frequency of differentiated immature monocyte-derived dendritic cells and naïve T cells was markedly increased in the mutant bone marrow. These phenotypes were quite different from those following β-catenin activation in mature osteoblasts driven by Col1a1-Cre (2.3-kb). Our findings suggested that a conserved pro-fibrotic signal cascade might underlie β-catenin-mediated bone marrow fibrosis, involving TGFβ1-enhanced fibrocyte activation and immunoregulatory responses. This study might shed new light on the understanding and development of a therapeutic strategy for bone fibrous dysplasia.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Cao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Li
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Shuqin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Rujiang
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: zjyao@sjtu.edu.cn.
authors.forename: Zhengju
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: xzguo2005@aliyun.com.
authors.forename: Xizhi
authors.initials: X
authors.lastname: Guo
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D024042:Collagen Type I / Q000378:metabolism; D005355:Fibrosis; D056747:Immunomodulation; D007249:Inflammation / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D013601:T-Lymphocytes / Q000473:pathology; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D051176:beta Catenin; C045073:Cre recombinase; D019426:Integrases
keywords: Bone marrow; Fibrosis; Immunoregulatory responses; TGFβ1; Wnt/β-catenin signaling