Role of osteoclasts in chronic inflammatory 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.破骨细胞（osteoclast）活性增强是多种慢性炎症性疾病（chronic inflammatory diseases）的标志性特征，同时伴随造血功能失调（dysregulated hematopoiesis）。然而，慢性结肠炎（chronic colitis）进程中，破骨细胞对造血功能异常的调控贡献仍未明确。本研究揭示了破骨细胞在结肠炎早期阶段可促进造血干细胞（hematopoietic stem cell, HSC）增殖，并诱导其发生显著髓系偏倚分化的意外作用。RNA测序（RNAseq）分析显示，结肠炎状态下的破骨细胞与对照组存在显著差异，其高表达参与骨吸收（bone resorption）及造血干细胞龛（HSC niches）重塑的相关基因。我们在体外实验中证实，结肠炎来源的破骨细胞可调控造血干细胞与其龛的相互作用，并促进髓系分化。在体内实验中，无论是小鼠模型还是慢性结肠炎患者体内，破骨细胞活性增强均与促炎性髓系细胞（pro-inflammatory myeloid cells）数量增加相关。在慢性结肠炎早期阶段直接体内抑制破骨细胞，可减少造血干细胞增殖及髓系偏倚，并降低临床评分（clinical score）与结肠炎疾病严重程度。综上，本研究证实破骨细胞是造血干细胞稳态的强效调控因子，或可成为结肠炎早期治疗的潜在靶点。