Liu F, Aubin J E, Malaval L
INSERM U403, Hôpital E. Herriot, Lyon, France.
Bone. 2002 Jul;31(1):212-9. doi: 10.1016/s8756-3282(02)00806-2.
The leukemia inhibitory factor/interleukin-6 (LIF/IL-6) family of cytokines is known to play a major role in bone physiology. Although much work has focused on the regulation of bone resorption by IL-6 and related cytokines, their effects on osteoblast development and bone formation have not been as well studied. Previously, we reported that LIF inhibits, in a non-IL-6-dependent manner, osteoblast differentiation and bone nodule formation in the rat calvaria (RC) model, an effect that is antagonized by dexamethasone (Dex). The culture time-sensitive window suggested that LIF targets late preosteoblasts or early osteoblasts, and that this stage-specific effect coincided with a period of low endogenous production of LIF and IL-6. To detect potential crosstalk between members of this family, we have extended these observations by assessing the expression levels of other LIF/IL-6 cytokines (CNTF, OSM, IL-11, CT-1) and their receptors in the same RC cell model treated with or without LIF or Dex. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that IL-11 and its receptor, CNTF and its receptor, LIFR, and gp130 were constitutively expressed throughout the culture period. Expression of CT-1 and OSM increased with culture time - that is, with osteoblast differentiation - whereas the specific receptor for OSM (OSMR) was highly expressed at early timepoints and either plateaued or decreased thereafter. Continuous treatment with Dex (10(-8) mol/L) inhibited the endogenous production of IL-6, LIF, OSM, IL-11R, and OSMR, but had no detectable effect on the expression of IL-11, CT-1, CNTF, CNTFR, LIFR, or gp130. Finally, treatment with exogenously added LIF stimulated IL-6, LIF, LIFR, and OSMR, but had no other detectable effects. These data indicate that multiple members of the LIF/IL-6 family and their receptors are expressed in RC cell cultures, and are differentially regulated by Dex and LIF, suggesting that these cytokines play a complex and interdependent role, further modulated by glucocorticoid levels, in osteoprogenitor differentiation and bone nodule formation.
白血病抑制因子/白细胞介素-6（LIF/IL-6）细胞因子家族在骨生理学中发挥着重要作用。尽管许多研究都集中在IL-6及相关细胞因子对骨吸收的调节上，但它们对成骨细胞发育和骨形成的影响尚未得到充分研究。此前，我们报道LIF以非IL-6依赖的方式抑制大鼠颅骨（RC）模型中的成骨细胞分化和骨结节形成，地塞米松（Dex）可拮抗这一作用。培养时间敏感窗口表明，LIF作用于晚期前成骨细胞或早期成骨细胞，且这种阶段特异性作用与LIF和IL-6内源性低水平产生的时期一致。为了检测该家族成员之间的潜在相互作用，我们通过评估在添加或不添加LIF或Dex的相同RC细胞模型中其他LIF/IL-6细胞因子（CNTF、OSM、IL-11、CT-1）及其受体的表达水平，扩展了这些观察结果。半定量逆转录-聚合酶链反应（RT-PCR）分析表明，IL-11及其受体、CNTF及其受体、LIFR和gp130在整个培养期间均有组成性表达。CT-1和OSM的表达随培养时间增加，即随着成骨细胞分化而增加，而OSM的特异性受体（OSMR）在早期时间点高表达，此后趋于平稳或下降。持续用Dex（10^(-8) mol/L）处理可抑制IL-6、LIF、OSM、IL-11R和OSMR的内源性产生，但对IL-11、CT-1、CNTF、CNTFR、LIFR或gp130的表达无明显影响。最后，外源性添加LIF刺激IL-6、LIF、LIFR和OSMR，但无其他明显作用。这些数据表明，LIF/IL-6家族的多个成员及其受体在RC细胞培养物中表达，并受到Dex和LIF的不同调节，提示这些细胞因子在骨祖细胞分化和骨结节形成中发挥复杂且相互依赖的作用，并进一步受糖皮质激素水平的调节。
