Role of osteoclasts in chronic inflammatory colitis. ORIOS_OCL_colitis

Increased osteoclast activity is a hallmark of many chronic inflammatory diseases in parallel with dysregulated hematopoiesis. However, the contribution of osteoclasts in altered hematopoiesis during chronic colitis remains unclear. Here, we identify an unexpected role of osteoclasts in promoting hematopoietic stem cell (HSC) proliferation and differentiation towards a substantial myeloid skewing in the early phases of colitis. RNAseq analysis revealed that osteoclasts in colitis differ from control ones and overexpress genes involved in bone resorption and the remodeling of HSC niches. We showed in vitro that colitic osteoclasts modulate the interaction of HSCs with their niche and promote myeloid differentiation. In vivo, increased osteoclast activity was associated with an augmentation in pro-inflammatory myeloid cells, both in mouse and in patients affected with chronic colitis. Direct inhibition of osteoclasts in vivo in the early stage of chronic colitis reduced HSC proliferation and myeloid skewing and resulted in a decreased of clinical score and severity of colitis. Together, these data identify osteoclasts as potent regulators of HSC homeostasis and may represent a promising target for the early treatment of colitis.