RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis.
RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis.
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DOI：
10.1002/art.39837
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发表时间：
2016-12
影响因子：
13.3
通讯作者：
Charles, Julia F.
中科院分区：
文献类型：
--
作者：
O'Brien, William;Fissel, Brian M.;Maeda, Yukiko;Yan, Jing;Ge, Xianpeng;Gravallese, Ellen M.;Aliprantis, Antonios O.;Charles, Julia F.
Pro-inflammatory molecules promote osteoclast-mediated bone erosion by upregulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as TNFα plus IL-6, induce RANKL-independent osteoclastogenesis. This study sought to better understand TNFα/IL-6 induced osteoclast formation, and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis. Myeloid precursors from wild-type (WT) mice, or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12 or Fcrg, were treated with either RANKL, or TNFα plus IL-6. Osteoprotegerin, anti-IL-6 receptor (IL6R) and hydroxyurea were used to block RANKL, the IL6R and cell proliferation, respectively. Clinical scoring, histology, micro-computed tomography and qPCR were employed to evaluate K/BxN serum transfer arthritis in WT and RANK-deleted mice. Loss of Rank was verified by qPCR and by performing osteoclast cultures. TNFα/IL-6 generated osteoclasts in vitro that resorbed mineralized tissue through a pathway dependent on IL6R, NFATc1, DAP12 and cell proliferation, but independent of RANKL or RANK. Bone erosion and osteoclast formation were reduced, but not absent, in arthritic mice with inducible deficiency of RANK. TNFα/IL-6, but not RANKL, induced osteoclast formation in bone marrow and synovial cultures from RANK-deficient animals. Multiple IL-6 family members (IL-6, LIF, OSM) were upregulated in the synovium of arthritic mice. The persistence of bone erosion and synovial osteoclasts in RANK-deficient mice, and the ability of TNFα/IL-6 to induce osteoclastogenesis, suggest more than one cytokine pathway exists to generate these bone resorbing cells in inflamed joints.
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影响因子：
6.2
作者：
Li, P;Schwarz, EM;Xing, LP
通讯作者：
Xing, LP
影响因子：
--
作者：
Nigrovic, Peter A.;Malbec, Odile;Lee, David M.
通讯作者：
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影响因子：
15.3
作者：
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影响因子：
4.4
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Okazaki, M;Yamada, Y;Mihara, M
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Mihara, M
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15.3
作者：
Kim, N;Kadono, Y;Choi, Y
通讯作者：
Choi, Y