Osteoclast activation by receptor activator of NF-κB ligand enhances the mobilization of hematopoietic progenitor cells from the bone marrow in acute injury

Abstract

Osteoclasts (OCLs) are multinucleated cells that are derived from the monocyte/macrophage hematopoietic lineage in response to receptor activator of NF-kappaB ligand (RANKL) activation. They are specialized cells responsible for physiological bone resorption and as well as pathologic bone loss. In addition to their unique ability to resorb bone, OCLs also play a potential role in the mobilization of hematopoietic progenitor cells from the bone marrow (BM), particularly under various stress stimuli (e.g. hypoxia, injury or inflammation). We investigated the effect of activated OCLs on the stem cell niche and whether this leads to mobilization of hematopoietic progenitors. We induced activated OCLs from the RAW264.7 cell line through stimulation with RANKL and we quantified the levels of the stem cell niche component SDF-1 on the osteblasts and CXCR4 on the bone marrow cells (BMCs) by culturing with supernatants from activated OCLs. In addition, we exposed mice to stress by inducing liver injury with CCl4 followed by injecting RANKL to activate OCLs and compared the effect on the mobilization of hematopoietic progenitor cells from the BM. We found that functional OCLs cleaved SDF-1alpha in the osteoblasts and increased CXCR4 expression in the BMCs. Moreover, under stress in vivo, mobilized hematopoietic progenitor cells were significantly increased after RANKL treatment. These results suggest that OCLs might be involved in alteration of the interaction between SDF-1 and CXCR4 leading to mobilization of hematopoietic progenitor cells from the BM.