Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice.
Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice.
复制标题
DOI：
--
复制
发表时间：
2004
影响因子：
--
通讯作者：
Ping Li;E. Schwarz;R. O’Keefe;Lin Ma;R. Looney;C. Ritchlin;B. Boyce;L. Xing
中科院分区：
文献类型：
--
作者：
Ping Li;E. Schwarz;R. O’Keefe;Lin Ma;R. Looney;C. Ritchlin;B. Boyce;L. Xing
目的探讨肿瘤坏死因子α（TNF α）促进破骨细胞生成的机制。方法采用TNF α转基因小鼠（TNF-Tg）和野生型小鼠，分别注射TNF α。使用脾细胞、外周血单核细胞（PBMC）和骨髓细胞进行体外破骨细胞生成试验、单核细胞集落形成试验和荧光激活细胞分选，以定量和表征破骨细胞前体（OCP）。TNF α拮抗剂依那西普用于体内阻断TNF α活性。使用5-溴-2 '-脱氧尿苷标记、膜联蛋白V染色和逆转录-聚合酶链反应评估TNF α对OCP增殖、凋亡和分化的影响。结果TNF-Tg小鼠外周血单个核细胞和脾脏中OCP数量增加4-7倍，而骨髓中OCP数量无明显增加。脾脏中的OCP在CD 11b（高）群体中，含有c-Fms-和c-Fms+细胞。OCP数量的增加与血清中可检测到的TNF α的起始和TNF-Tg小鼠中炎性关节炎的发作相关。依那西普消除了外周OCP的增加。TNF α在体内或体外均不影响CD 11b（高）脾细胞的增殖、存活或分化，但在单次注射后4小时内导致血液中CD 11b+细胞迅速增加，在多次注射后3天导致脾脏中CD 11b（高）OCP蓄积。结论全身性TNF α诱导循环中OCP的显著增加，这种增加可被抗TNF治疗逆转，可能是由于它们从骨髓中动员所致。我们的研究结果提供了一个新的机制，TNF α刺激破骨细胞在炎症性关节炎患者，这表明CD 11b + PBMC可用于评估患者的潜在侵蚀性疾病和抗TNF治疗的疗效。
OBJECTIVE To investigate the mechanisms whereby tumor necrosis factor alpha (TNFalpha) increases osteoclastogenesis in vivo. METHODS TNFalpha-transgenic (TNF-Tg) and wild-type mice injected with TNFalpha were studied. In vitro osteoclastogenesis assays, monocyte colony-forming assays, and fluorescence-activated cell sorting were performed using splenocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells to quantify and characterize osteoclast precursors (OCPs). Etanercept, a TNFalpha antagonist, was used to block TNFalpha activity in vivo. The effects of TNFalpha on proliferation, apoptosis, and differentiation of OCPs were assessed using 5-bromo-2'-deoxyuridine labeling, annexin V staining, and reverse transcriptase-polymerase chain reaction. RESULTS OCP numbers were increased 4-7-fold in PBMCs and spleen, but not in bone marrow of TNF-Tg mice. The OCPs in spleen were in the CD11b(high) population and contained both c-Fms- and c-Fms+ cells. The increased number of OCPs correlated with the initiation of detectable TNFalpha in serum and the onset of inflammatory arthritis in TNF-Tg mice. Etanercept eliminated the increase in peripheral OCPs. TNFalpha did not affect proliferation, survival, or differentiation of CD11b(high) splenocytes in vivo or in vitro, but caused a rapid increase in CD11b+ cells in blood within 4 hours of a single injection and an accumulation of CD11b(high) OCPs in spleen after 3 days of multiple injections. CONCLUSION Systemic TNFalpha induces a marked increase in circulating OCPs that is reversible by anti-TNF therapy and may result from their mobilization from bone marrow. Our findings provide a new mechanism whereby TNFalpha stimulates osteoclastogenesis in patients with inflammatory arthritis, suggesting that CD11b+ PBMCs could be used to evaluate a patient's potential for erosive disease and the efficacy of anti-TNF therapy.