Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia-Inducible Factor 1α and E2F1.
Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia-Inducible Factor 1α and E2F1.
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DOI：
10.1002/art.42074
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发表时间：
2022-06
影响因子：
13.3
通讯作者：
Matsuda, Shuichi
中科院分区：
文献类型：
--
作者：
Doi, Kohei;Murata, Koichi;Ito, Shuji;Suzuki, Akari;Terao, Chikashi;Ishie, Shinichiro;Umemoto, Akio;Murotani, Yoshiki;Nishitani, Kohei;Yoshitomi, Hiroyuki;Fujii, Takayuki;Watanabe, Ryu;Hashimoto, Motomu;Murakami, Kosaku;Tanaka, Masao;Ito, Hiromu;Park-Min, Kyung-Hyun;Ivashkiv, Lionel B.;Morinobu, Akio;Matsuda, Shuichi
缺氧发生在肿瘤、感染和炎症部位，如类风湿性关节炎（RA）患者的关节。在炎症性关节炎中，它通过促进破骨细胞的生成来减轻炎症反应并增加骨吸收。缺氧反应与破骨细胞生成和炎性骨吸收相关的机制尚不清楚。我们发现LSD 1代谢整合炎性破骨细胞生成和骨吸收。使用LSD 1特异性抑制剂和siRNA来抑制LSD 1。使用来源于CD 14+细胞的人破骨细胞前体，进行RNA测序和后续分析。以加速性骨丢失模型和炎性骨溶解模型作为小鼠模型。在对HIF-1α进行顺式表达数量性状基因座（cis-eQTL）分析后，评估了RA患者中HIF-1α等位基因变异体与骨侵蚀的相关性。RANKL以mTOR依赖性方式诱导LSD 1表达。LSD 1在类风湿关节炎滑膜中的表达高于骨关节炎滑膜。LSD 1抑制抑制破骨细胞分化。转录组分析确定LSD 1介导的缺氧和细胞周期途径在人类破骨细胞生成。此外，HIF-1α蛋白在正常氧下被蛋白酶体快速降解，在RANKL刺激的破骨细胞前体细胞中表达。RANKL诱导的LSD 1稳定HIF-1α蛋白，从而促进糖酵解，沿着E2 F1，后者也被LSD 1上调。cis-eQTL分析显示HIF-1α的高表达与RA患者骨质侵蚀的增加相关。在加速骨质疏松症小鼠模型以及关节炎和炎性骨质溶解小鼠模型中，LSD 1抑制降低了病理性骨吸收。LSD 1在炎性能量需求环境中代谢调节破骨细胞生成，并提供针对破骨细胞对抗炎性关节炎（包括RA）的新治疗策略。
Hypoxia occurs in tumors, infections, and inflammatory sites such as joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. We showed that LSD1 metabolically integrates inflammatory osteoclastogenesis and bone resorption. LSD1 specific inhibitors and siRNAs were used to inhibit LSD1. Using human osteoclast precursors derived from CD14+ cells, RNA-sequencing and subsequent analysis were performed. Accelerated bone loss and inflammatory osteolysis models were tested as mice model. After cis-expression quantitative trait locus (cis-eQTL) analysis for HIF-1α, the association between HIF-1α allelic variants bone erosion was evaluated in RA patients. RANKL induces LSD1 expression in an mTOR-dependent manner. The expression of LSD1 was higher in RA synovium than that from osteoarthritis. LSD1 inhibition suppresses osteoclast differentiation. Transcriptome analysis identified LSD1-mediated hypoxia and cell-cycle pathways during human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in normoxia, was expressed in RANKL-stimulated osteoclast precursor cells. RANKL-induced LSD1 stabilized HIF-1α protein, thereby promoted glycolysis, along with E2F1, which was also upregulated by LSD1. cis-eQTL analysis revealed that higher HIF-1α expression was associated with increased bone erosion in RA. LSD1 inhibition decreased pathological bone resorption in an accelerated osteoporosis mouse model and arthritis and inflammatory osteolysis mouse models. LSD1 metabolically regulates osteoclastogenesis in an inflammatory energy-demanding environment and provides new therapeutic strategies targeting osteoclasts against inflammatory arthritis including RA.
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影响因子：
5.7
作者：
Pishas KI;Drenberg CD;Taslim C;Theisen ER;Johnson KM;Saund RS;Pop IL;Crompton BD;Lawlor ER;Tirode F;Mora J;Delattre O;Beckerle MC;Callen DF;Sharma S;Lessnick SL
通讯作者：
Lessnick SL
DOI：
10.1002/art.40504
发表时间：
2018-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Falconer J;Murphy AN;Young SP;Clark AR;Tiziani S;Guma M;Buckley CD
通讯作者：
Buckley CD
影响因子：
32.4
作者：
Palazon, Asis;Goldrath, Ananda W.;Nizet, Victor;Johnson, Randall S.
通讯作者：
Johnson, Randall S.
影响因子：
--
作者：
Cimmino, Flora;Avitabile, Marianna;Capasso, Mario
通讯作者：
Capasso, Mario
影响因子：
64.8
作者：
Rius, Jordi;Guma, Monica;Karin, Michael
通讯作者：
Karin, Michael