IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice
IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice
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DOI：
10.4049/jimmunol.181.8.5720
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发表时间：
2008-10-15
影响因子：
4.4
通讯作者：
Gillespie, Matthew T.
中科院分区：
文献类型：
--
作者：
Quinn, Julian M. W.;Sims, Natalie A.;Gillespie, Matthew T.
IL-23刺激CD 4（+）T细胞Th 17亚群的分化和功能，并在慢性炎症中起关键作用。IL-23受体编码基因也是炎性疾病易感基因。IL-23与IL-12（一种T细胞依赖性破骨细胞形成抑制剂）共享一个共同的亚基，我们发现IL-23也以CD 4（+）T淋巴细胞依赖性方式剂量依赖性地抑制破骨细胞生成。当充分富集时，γ δ T细胞也介导IL-23抑制。与IL-12一样，IL-23与IL-18协同作用以阻断破骨细胞生成，但与IL-12不同，IL-23的作用依赖于T细胞GM-CSF的产生。IL-23不介导IL-12的作用，虽然IL-12诱导其表达。缺乏IL-23（IL-23 p19（-/-））的雄性小鼠在12周龄时的骨矿物质密度和胫骨小梁骨量（骨体积（BV）/总体积（TV））比野生型同窝小鼠低30%，在26周龄时BV/TV低40%;雄性杂合子的骨量也较低。雌性IL-23 p19（-/-）小鼠也具有降低的BV/TV。IL-23 p19（-/-）小鼠在骨小梁中没有可检测到的破骨细胞缺陷，但与野生型相比，IL-23 p19（-/-）具有更薄的生长板肥大和初级海绵状带（并且，在雌性中，软骨残留更少）。这表明在生长板处和生长板下方破骨细胞作用增加，导致成熟骨小梁数量减少。因此，IL-23在体外通过T细胞间接抑制破骨细胞形成。在非病理条件下（与炎性条件不同），IL-23通过限制生长板下形成的未成熟骨的再吸收而有利于长骨中较高的骨量。
IL-23 stimulates the differentiation and function of the Th17 subset of CD4(+) T cells and plays a critical role in chronic inflammation. The IL-23 receptor-encoding gene is also an inflammatory disease susceptibility gene. IL-23 shares a common subunit with IL-12, a T cell-dependent osteoclast formation inhibitor, and we found that IL-23 also dose-dependently inhibited osteoclastogenesis in a CD4(+) T lymphocyte-dependent manner. When sufficiently enriched, gamma delta T cells also mediated IL-23 inhibition. Like IL-12, IL-23 acted synergistically with IL-18 to block osteoclastogenesis but, unlike IL-12, IL-23 action depended on T cell GM-CSF production. IL-23 did not mediate IL-12 action although IL-12 induced its expression. Male mice lacking IL-23 (IL-23p19(-/-)) had similar to 30% lower bone mineral density and tibial trabecular bone mass (bone volume (BV)/total volume (TV)) than wild-type littermates at 12 wk and 40% lower BV/TV at 26 wk of age; male heterozygotes also had lower bone mass. Female IL-23p19(-/-) mice also had reduced BV/TV. IL-23p19(-/-) mice had no detectable osteoclast defect in trabecular bone but IL-23p19(-/-) had thinner growth plate hypertrophic and primary spongiosa zones (and, in females, less cartilage remnants) compared with wild type. This suggests increased osteoclast action at and below the growth plate, leading to reduced amounts of mature trabecular bone. Thus, IL-23 inhibits osteoclast formation indirectly via T cells in vitro. Under nonpathological conditions (unlike inflammatory conditions), IL-23 favors higher bone mass in long bones by limiting resorption of immature bone forming below the growth plate.