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Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-08-11 , DOI: 10.1073/pnas.2006093117
Quang Tien Phan 1, 2 , Wen Hui Tan 1, 2 , Ranran Liu 1, 2 , Sudha Sundaram 1, 2 , Anita Buettner 1, 2 , Susanne Kneitz 3 , Benedict Cheong 1, 2 , Himanshu Vyas 1, 2 , Sinnakaruppan Mathavan 4, 5 , Manfred Schartl 3, 6 , Christoph Winkler 2, 7
Affiliation  

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.



中文翻译:

Cxcl9l和Cxcr3.2在medaka骨质疏松症模型中调节破骨细胞祖细胞向骨基质的募集。

骨稳态需要连续重建骨基质以维持结构完整性。这涉及成骨的成骨细胞与骨吸收的破骨细胞之间的广泛交流,以协调平衡的祖细胞募集和活化。迄今为止,仅少数控制祖细胞活化的介体是已知的,并且已被靶向用于骨疾病如骨质疏松症的干预。为了确定可药物化的途径,我们产生了一种aka(Oryzias latipes)骨质疏松症模型,其中核因子kappa-Β配体(Rankl)受体激活剂的可诱导表达导致破骨细胞异位形成和骨吸收过多,可通过实时成像进行评估。在这里,我们显示在Rankl诱导后,成骨祖细胞上调趋化因子配体Cxcl9l的表达。Cxcl9l的异位表达将mpeg1阳性巨噬细胞募集至骨基质,并触发其分化为破骨细胞。我们还证明了趋化因子受体Cxcr3.2在主动脉-性腺-中肾(AGM)中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,迁移至骨基质,并分化为破骨细胞。重要的是,cxcr3.2中的突变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的抑制作用还减少了破骨细胞的募集并保护了骨质抵抗骨质疏松性损伤。我们的数据确定了祖细胞募集到骨吸收位点的机制以及Cxcl9l和Cxcr3.2作为骨稳态和骨质疏松症的潜在药物调节剂。

更新日期:2020-08-11
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