Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice.
Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice.
复制标题
淋巴内皮细胞产生 M-CSF，导致小鼠大量骨质流失
DOI：
10.1002/jbmr.3077
复制
发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Xing L
中科院分区：
文献类型：
--
作者：
Wang W;Wang H;Zhou X;Li X;Sun W;Dellinger M;Boyce BF;Xing L
Gorham-Stout病（GSD）是一种罕见的骨疾病，其特征是与骨髓腔内淋巴管浸润相关的侵袭性骨质溶解。GSD的病因尚不清楚，也没有有效的治疗方法或动物模型。在这里，我们研究了淋巴管内皮细胞（LEC）是否影响破骨细胞（OC）导致小鼠GSD溶骨性表型。我们研究了小鼠LEC系在共培养中对破骨细胞生成的影响。LEC显著增加RANKL介导的OC形成和骨吸收。LEC表达高水平的M-CSF，但不表达RANKL、IL-6和TNF。LEC介导的OC形成和骨吸收被M-CSF中和抗体或Ki 20227（M-CSF受体c-Fms的抑制剂）阻断。我们将LEC注射到WT小鼠的胫骨中，并在X射线和显微CT扫描上观察到大量的骨溶解。组织学显示，LEC注射的钛具有显著的骨小梁和皮质骨丢失以及OC数量增加。M-CSF蛋白水平显着较高的小鼠血清和骨髓血浆给予胫骨LEC注射。免疫荧光染色显示podoplanin+ LEC广泛替代了骨和骨髓。用Ki 20227治疗LEC注射的小鼠显著降低胫骨破坏。此外，GSD骨样本中的淋巴管对M-CSF染色呈阳性。因此，LEC通过分泌促进OC形成和活化的M-CSF在小鼠体内引起骨破坏。阻断M-CSF信号转导可能代表治疗GSD患者的新治疗方法。此外，胫骨注射LEC是一个有用的小鼠模型，研究GSD。
Gorham-Stout disease (GSD) is a rare bone disorder characterized by aggressive osteolysis associated with lymphatic vessel invasion within bone marrow cavities. The etiology of GSD is not known and there is no effective therapy or animal model for the disease. Here, we investigated if lymphatic endothelial cells (LECs) affect osteoclasts (OCs) to cause a GSD osteolytic phenotype in mice. We examined the effect of a mouse LEC line on osteoclastogenesis in co-cultures. LECs significantly increased RANKL-mediated OC formation and bone resorption. LECs expressed high levels of M-CSF, but not RANKL, IL-6 and TNF. LEC-mediated OC formation and bone resorption were blocked by an M-CSF neutralizing antibody or Ki20227, a inhibitor of the M-CSF receptor, c-Fms. We injected LECs into the tibiae of WT mice and observed massive osteolysis on X-ray and micro-CT scans. Histology showed that LEC-injected tibiae had significant trabecular and cortical bone loss and increased OC numbers. M-CSF protein levels were significantly higher in serum and bone marrow plasma of mice given intra-tibial LEC injections. Immunofluorescence staining showed extensive replacement of bone and marrow by podoplanin+ LECs. Treatment of LEC-injected mice with Ki20227 significantly decreased tibial bone destruction. In addition, lymphatic vessels in a GSD bone sample were stained positively for M-CSF. Thus, LECs cause bone destruction in vivo in mice by secreting M-CSF, which promotes OC formation and activation. Blocking M-CSF signaling may represent a new therapeutic approach for treatment of patients with GSD. Furthermore, tibial injection of LECs is a useful mouse model to study GSD.