Bone marrow fibrosis with fibrocytic and immunoregulatory responses induced by ß-catenin activation in osteoprogenitors.

ABSTRACT

Wnt/ß-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 ß-catenin-mediated bone marrow fibrosis. In this study, we showed that constitutive activation of ß-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, ß-catenin stimulated the secretion of cytokines and pro-fibrotic signals in bone marrow, including GM-CSF, TGFß1 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 ß-catenin activation in mature osteoblasts driven by Col1a1-Cre (2.3-kb). Our findings suggested that a conserved pro-fibrotic signal cascade might underlie ß-catenin-mediated bone marrow fibrosis, involving TGFß1-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.