Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.

译文

骨内稳态需要不断重塑骨基质以保持结构完整性。这涉及成骨成骨细胞和骨吸收破骨细胞之间的广泛交流,以协调平衡的祖细胞募集和激活。迄今为止,只有少数控制祖细胞激活的介体已知,并且已被靶向干预骨质疏松等骨骼疾病。为了确定可药物治疗的途径,我们建立了一个medaka (Oryzias latipes) 骨质疏松模型,其中核因子 κ-β 配体 (Rankl) 受体激活剂的诱导表达导致破骨细胞异位形成和过度的骨吸收,这可以通过实时成像进行评估。在这里,我们显示在Rankl诱导后,成骨细胞祖细胞上调趋化因子配体Cxcl9l的表达。Cxcl9l的异位表达将mpeg1-positive巨噬细胞募集到骨基质并触发其分化为破骨细胞。我们还证明趋化因子受体Cxcr3.2在主动脉-性腺-中肾 (AGM) 的巨噬细胞的不同子集中表达。实时成像显示,在Rankl诱导后,Cxcr3.2阳性巨噬细胞被激活,迁移到骨基质并分化为破骨细胞。重要的是,cxcr3.2中的突变可防止巨噬细胞募集和破骨细胞分化。此外,化学拮抗剂AMG487和NBI-74330对Cxcr3.2的抑制也减少了破骨细胞的募集,并保护了骨完整性免受骨质疏松损伤。我们的数据确定了将祖细胞募集到骨吸收位点的机制,Cxcl9l和Cxcr3.2是骨稳态和骨质疏松症的潜在可药物调节剂。

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