Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling.
Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling.
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DOI：
10.1038/s41413-017-0006-3
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发表时间：
2018
期刊：
影响因子：
12.7
通讯作者：
Niemeier A
中科院分区：
文献类型：
--
作者：
Bartelt A;Behler-Janbeck F;Beil FT;Koehne T;Müller B;Schmidt T;Heine M;Ochs L;Yilmaz T;Dietrich M;Tuckermann JP;Amling M;Herz J;Schinke T;Heeren J;Niemeier A
骨骼健康依赖于结构完整性和足够的骨量，这是通过破骨细胞的骨吸收和成骨细胞的骨形成的严格调节平衡来维持的。遗传学研究已经将编码低密度脂蛋白受体相关蛋白1（Lrp 1）的基因与骨骼性状联系起来，但这些联系是否基于因果分子关系尚不清楚。在这里，我们表明，Lrp 1在成骨细胞是一种新的调节破骨细胞活性和骨量。在成骨细胞谱系中缺乏Lrp 1的小鼠表现出正常的成骨细胞功能，但由于破骨细胞数量和骨吸收的高度增加而导致严重的骨质疏松症。成骨细胞Lrp 1通过减弱血小板源性生长因子（PDGF-BB）信号传导限制体内和体外NF-κB配体（RANKL）受体激活因子表达。在共培养中，Lrp 1缺陷型成骨细胞以PDGFRβ依赖性方式刺激破骨细胞生成，并且用PDGFR酪氨酸激酶抑制剂甲磺酸伊马替尼体内处理限制了RANKL的产生，并导致骨质疏松表型的完全缓解。这些结果确定成骨细胞Lrp 1是成骨细胞与破骨细胞之间通过成骨细胞中的PDGF-RANKL信号传导轴进行通讯和骨量的关键调节因子，并为进一步探索PDGF信号传导抑制剂在抵消骨丢失方面的潜力以及评估功能性LRP 1基因变体在控制人类骨量中的重要性开辟了前景。保持骨骼强壮主要取决于低密度脂蛋白的受体（Lrp 1）。骨骼不断重塑，成骨细胞增加新骨，破骨细胞吸收旧骨。不平衡的生长和吸收可导致骨质疏松症。遗传学研究以前曾将Lrp 1与骨骼健康联系起来，但这种联系的性质仍然未知。德国汉堡-埃彭多夫大学医学中心的Andreas Niemeier及其同事使用成骨细胞缺乏Lrp 1的模型小鼠来研究受体如何参与骨转换。Lrp-1缺陷小鼠表现出严重的骨质疏松症。他们还显示破骨细胞的数量很高，但成骨细胞的数量正常，这表明缺乏受体会导致骨吸收增加。用与Lrp 1相关的药物治疗小鼠恢复了骨强度。这些结果可能有助于确定新的治疗骨质流失的方法。
Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1 (Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass. Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand (RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor (PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF–RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans. Maintaining strong bones critically depends on a receptor (Lrp1) for low-density lipoprotein. Bones are continually remodeled, with osteoblast cells adding new bone and osteoclast cells resorbing old bone. Imbalanced growth and resorption can lead to osteoporosis. Genetic studies had previously linked Lrp1 to bone health, but the nature of the link remained unknown. Andreas Niemeier at the University Medical Center Hamburg-Eppendorf in Germany and co-workers used model mice whose osteoblasts lacked Lrp1 to investigate how the receptor is involved in bone turnover. Lrp-1-deficient mice showed severe osteoporosis. They also showed high numbers of osteoclasts but normal numbers of osteoblasts, indicating that lack of the receptor caused increased bone resorption. Treatment of the mice with a drug related to Lrp1 restored bone strength. These results may help to identify new treatments for bone loss.
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