Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease
Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease
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DOI：
10.1038/s41467-019-12296-1
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发表时间：
2019-10-04
影响因子：
16.6
通讯作者：
Edwards, Claire M.
中科院分区：
文献类型：
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作者：
Gooding, Sarah;Olechnowicz, Sam W. Z.;Edwards, Claire M.
多发性骨髓瘤是一种无法治愈的骨髓恶性肿瘤，会破坏骨稳态，导致骨骼损伤和疼痛。骨髓瘤引起的骨破坏的机制尚不清楚，目前的治疗方法不能恢复丢失的骨量。通过对小鼠骨髓瘤模型中分离的骨衬细胞亚型进行转录组学分析，我们发现基质祖细胞中骨形态发生蛋白（BMP）信号传导上调。此前尚未有报道称 BMP 信号在骨髓瘤骨病中失调。使用小分子 BMP 受体拮抗剂或溶解的 BMPR1a-FC 受体配体陷阱抑制体内 BMP 信号传导，可防止骨髓瘤引起的小梁骨和皮质骨体积损失，而不会增加肿瘤负担。 BMP 抑制直接减少破骨细胞生成，增加成骨细胞和骨形成，并抑制骨髓硬化素水平。总之，我们描述了 BMP 通路在骨髓瘤诱发的骨病中的新作用，可以作为治疗目标。
Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted.