Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice
Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice
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DOI：
10.1016/j.joca.2018.11.008
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发表时间：
2019-03-01
影响因子：
7
通讯作者：
Monteagudo, S.
中科院分区：
文献类型：
--
作者：
Cornelis, F. M. F.;de Roover, A.;Monteagudo, S.
目的：我们之前发现端粒沉默组蛋白甲基转移酶干扰物 1 样 (DOT1L) 通过限制 Wnt 通路的过度激活而成为软骨健康的主要保护者。然而，软骨特异性纯合 Dot1l 敲除小鼠表现出严重的生长表型和围产期死亡，这阻碍了它们在诱导或衰老骨关节炎 (OA) 模型中的使用。本研究的目的是生成和检查单倍体不足和可诱导的条件性 Dot1l 缺陷小鼠模型，以评估 DOT1L 在创伤后或衰老相关 OA 发病和进展过程中的重要性。方法：我们使用软骨特异性杂合和出生后他莫昔芬诱导的 Dot1l 敲除小鼠，并对内侧进行去稳定 半月板 (DMM) 和衰老作为 OA 模型。使用 X 射线和微型计算机断层扫描 (mu CT) 对小鼠进行组织学检查，并根据 OARSI 指南评估软骨损伤和骨赘形成。对 DOT1L、H3K79me2、TCF1 和 COLX 进行了免疫组织化学分析。结果：两种 Dot1L 缺陷菌株均表现出以关节重塑为特征的表型，伴随着衰老时广泛的骨赘形成和异位骨化，表明自发性骨关节炎的加速发展。在 DMM 诱导的 OA 小鼠模型中，Dot1l 的缺失导致软骨损伤增加。在两只 Dot1l 缺陷小鼠的关节软骨中观察到 Wnt 信号过度激活和异位软骨细胞肥大。结论：本研究使用转基因小鼠证明了 DOT1L 在 OA 发展过程中体内的功能相关性。因此，在衰老过程中或创伤后维持或增强 DOT1L 活性可能会预防 OA 的发生和进展。 (c) 2018 年国际骨关节炎研究协会。由爱思唯尔有限公司出版。保留所有权利。
Objective: We earlier identified that the histone methyltransferase Disruptor of telomeric silencing 1-like (DOT1L) is as a master protector of cartilage health via limiting excessive activation of the Wnt pathway. However, cartilage-specific homozygous Dot1l knockout mice exhibited a severe growth phenotype and perinatal death, which hampered their use in induced or ageing models of osteoarthritis (OA). The aim of this study was to generate and examine haploinsufficient and inducible conditional Dot1l-deficient mouse models to evaluate the importance of DOT1L during post-traumatic or ageing-associated OA onset and progression.Method: We used cartilage-specific heterozygous and postnatal tamoxifen-inducible Dot1l knockout mice and performed destabilization of the medial meniscus (DMM) and ageing as OA models. Mice were examined histologically using X-rays and micro-computed tomography (mu CT), and cartilage damage and osteophyte formation were assessed based on OARSI guidelines. Immunohistochemistry of DOT1L, H3K79me2, TCF1 and COLX was performed.Results: Both Dot1l-deficient strains exhibit a phenotype characterized by joint remodeling with extensive osteophyte formation and ectopic ossification upon ageing, indicating accelerated development of spontaneous osteoarthritis. In the DMM-induced OA mouse model, absence of Dot1l resulted in increased cartilage damage. Wnt signalling hyper-activation and ectopic chondrocyte hypertrophy were observed in the articular cartilage of both Dot1l-deficient mice.Conclusions: This study demonstrated the functional relevance of DOT1L in vivo during the development of OA using genetically modified mice. Thus, maintaining or enhancing DOT1L activity during ageing or after trauma might prevent OA onset and progression. (c) 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.