Role of Chitinase 3-like-1 in Myelofibrosis via Fibroblast-Produced Extracellular Matrix Enhancement

Cluster of differentiation 14⁺ monocytes produced spindle-shaped fibrocytes, similar to fibroblasts. Recent studies have reported that fibrocytes are crucial for the development and progression of primary myelofibrosis (MF); however, their functional role remains unclear. We compared monocytes and fibrocytes using RNA sequencing for gene expression profiles. We focused on chitinase 3-like-1 (CHI3L1), which causes inflammation, organ fibrosis, and extracellular tissue remodeling. We found higher CHI3L1 levels in patients with myeloproliferative neoplasm with MF than in those without MF. Further, serum CHI3L1 levels were significantly associated with the presence of MF and splenomegaly in patients with lymphoid tumors. Romiplostim-induced MF in a mouse model demonstrated extensive bone marrow (BM) CHI3L1 mRNA expression, which was reversed by clodronate treatment. Two MF induction experiments on CHI3L1^-/- mice, based on romiplostim or Janus kinase 2 mutations, revealed fewer reticular fibers in silver-stained BM slices than in wild-type mice. A culture assay revealed that high CHI3L1 concentrations promoted extracellular matrix production by fibroblast cell lines, and that a CHI3L1-neutralizing antibody abrogated this effect. These results indicate the importance of CHI3L1 in the association between fibrocytes and fibroblasts in MF and could be a focus for future treatment.