By contrast, several reports have demonstrated that OSM induces osteogenic differentiation of human MSC and a murine stromal cell line, suggesting a role for OSM in the hematopoietic microenvironment. In this report, we aimed to unravel the roles of OSM in the BM hematopoietic microenvironment under various conditions, BM injuries by chemicals or irradiation and aging. In addition, we prepared PaS MSC from WT and OSMR KO BM to examine the biological activities of OSM in their adipogenic and osteogenic differentiation and evaluated the hematopoietic capacity by developing a co-culture system with HSPC. We further present the possibility to use OSM as a promising therapeutic agent to enhance the recovery of hematopoiesis after BM lesion. Our results demonstrate that OSM contributes to the maintenance of the hematopoietic microenvironment by balancing multiple steps of differentiation of BM MSC in both steady and injured states. In the present study, we focused on the effect of OSM on PaS cell because the cell has been reported to differentiate into hematopoietic niche cells, osteoblasts, and adipocytes after in vivo transplantation. We demonstrated that OSM exhibits distinct biological activities against adipogenesis and osteogenesis of PaS cells. We previously reported the inhibitory effect of OSM on the adipocytic differentiation of AB1010 3T3-L1, a preadipocyte line and that both OSM KO and OSMR KO mice displayed an anemic phenotype Palbociclib accompanied by the reduction of hematopoietic activity in the BM. Here, we showed that OSM is expressed constitutively and abundantly in the BM, a unique feature of OSM among the IL-6 family cytokines. Moreover, the adipogenesis in OSM KO BM was accelerated with age as well as after myeloablation. These results strongly suggest that OSM plays a critical role in the development and/or maintenance of the BM microenvironment. Considering that adipogenic change occurs drastically and extensively in the BM after irradiation and that PaS cells are relatively rare in marrow cavities, OSM may contribute to hematopoietic microenvironment by affecting the other type of BM MSC as well as PaS cells. Adipocytes in the BM are considered to be a negative regulator of the hematopoietic microenvironment, raising the possibility that the administration of a chemical inhibitor of adipogenesis might enhance marrow engraftment and hematopoietic recovery after irradiation by antagonizing BM adipogenesis. Therefore, the regulatory mechanisms underlying BM adipogenesis in the steady state as well as under disease conditions would help us to understand the hematopoietic microenvironment and develop novel therapeutic strategies.