Role of FLT3 ITD PTPRC signaling in bone remodeling

Bone remodeling is a continuous process that occurs at every bone surface and helps to maintain the skeletal shape and quality. It involves osteoclasts, derived from the hematopoietic lineage, which initially resorb bone, followed by osteoblasts, derived from the mesenchymal lineage, which form new bone. A mouse model combining an oncogenic internal tandem duplication (ITD) mutation in the Flt3 gene with inactivation of PTPRC activity showed abnormal bone structures with increased numbers of trabeculae. Furthermore, osteoclast and osteoblast numbers were altered in the femur of these mice compared to controls. Osteoclast differentiation was impaired in cells derived from mice carrying FLT3 ITD and the inactivation of PTPRC. During osteoclast differentiation, proliferation of these cells was higher compared to the controls, which was due to FLT3 ITD activity and its downstream target STAT5. The effect of FLT3 ITD and knockout of Ptprc on osteoblast differentiation was less substantial compared to the effect on osteoclasts. However, mineralization activity of osteoblasts was reduced. Analysis of gene expression in both osteoclasts and osteoblasts indicated a dysregulated crosstalk between these cell types, affecting multiple signaling pathways that influence osteoclast differentiation, osteoblast differentiation, and coupling of bone resorption and formation during bone remodeling. In conclusion, the presence of oncogenic FLT3 ITD in combination with the absence of PTPRC in mice led to alterations in the osteohematopoietic niche. These alterations affected the proliferation and differentiation processes of hematopoietic and mesenchymal cells, thereby affecting osteoclast and osteoblast activity, bone remodeling and causing a severe bone phenotype.