Research Article: Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Date Published: March 24, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Ying‐Jie Guan, Jing Li, Xu Yang, Shaohua Du, Jing Ding, Yun Gao, Ying Zhang, Kun Yang, Qian Chen.


Primary osteoarthritis (OA) is associated with aging, while post‐traumatic OA (PTOA) is associated with mechanical injury and inflammation. It is not clear whether the two types of osteoarthritis share common mechanisms. We found that miR‐146a, a microRNA‐associated with inflammation, is activated by cyclic load in the physiological range but suppressed by mechanical overload in human articular chondrocytes. Furthermore, miR‐146a expression is decreased in the OA lesions of human articular cartilage. To understand the role of miR‐146a in osteoarthritis, we systemically characterized mice in which miR‐146a is either deficient in whole body or overexpressed in chondrogenic cells specifically. miR‐146a‐deficient mice develop early onset of OA characterized by cartilage degeneration, synovitis, and osteophytes. Conversely, miR‐146a chondrogenic overexpressing mice are resistant to aging‐associated OA. Loss of miR‐146a exacerbates articular cartilage degeneration during PTOA, while chondrogenic overexpression of miR‐146a inhibits PTOA. Thus, miR‐146a inhibits both OA and PTOA in mice, suggesting a common protective mechanism initiated by miR‐146a. miR‐146a suppresses IL‐1β of catabolic factors, and we provide evidence that miR‐146a directly inhibits Notch1 expression. Therefore, such inhibition of Notch1 may explain suppression of inflammatory mediators by miR‐146a. Chondrogenic overexpression of miR‐146a or intra‐articular administration of a Notch1 inhibitor alleviates IL‐1β‐induced catabolism and rescues joint degeneration in miR‐146a‐deficient mice, suggesting that miR‐146a is sufficient to protect OA pathogenesis by inhibiting Notch signaling in the joint. Thus, miR‐146a may be used to counter both aging‐associated OA and mechanical injury‐/inflammation‐induced PTOA.

Partial Text

Osteoarthritis (OA), the most prevalent aging‐related joint disease worldwide, is a major cause of disability that carries an extremely high socioeconomic burden (Hunter, Schofield & Callander, 2014). Osteoarthritis usually manifests as degeneration of articular cartilage, but other joint tissues, such as subchondral bone and the synovial membranes, are also affected. These alterations are responsible for pain, joint failure, and loss of joint architectural integrity. Current treatments for OA are limited to pain management and, in the late phase of the disease process, joint‐replacement surgery (Loeser, Goldring, Scanzello & Goldring, 2012). There are two major forms of OA. While primary OA occurs in response to slow but steady increase in inflammation during aging, secondary OA is trigged by trauma‐induced mechanical damage. Thus, mechanical overload and inflammation are two major extrinsic factors causing OA (Lotz & Kraus, 2010). Most of these disease outcomes are associated with abnormal differentiation of chondrocytes coupled with an imbalance in the turnover of cartilaginous extracellular matrix (ECM). Although genetic factors have been implicated in the pathogenesis of OA, the epigenetic pathways that precisely regulate the catabolic or anabolic responses and the balance of these processes are just beginning to be understood (Reynard & Loughlin, 2013). Understanding the molecular mechanisms to maintain joint cartilage homeostasis will be extremely important for developing future disease‐modifying OA drugs (DMOADs).

While genetics accounts for about 50% of OA pathogenesis, the other 50% is due to other factors including epigenetics (Im & Choi, 2013). It becomes clear that multiple environmental factors are critical to epigenetic regulation of OA. They include aging, inflammation, and joint mechanics (Loeser, Collins & Diekman, 2016). However, it is not clear how these diverse factors regulate epigenetics of OA. MicroRNAs are posttranscriptional regulators of gene expression that control a wide range of biological processes (Selbach et al., 2008). We demonstrate in this study that miR‐146a may be a key factor that regulates OA pathogenesis by responding to aging, inflammation, and mechanical loading, thereby potentially linking these diverse OA‐driving factors. We were the first to identify miR‐146a as a mechanoresponsive microRNA along with miR‐365 through cytomechanical screening of microRNA microarray (Guan, Yang, Wei & Chen, 2011). Since then, multiple studies have supported the role of miR‐146a as a mechano‐miR (Huang, Crawford, Higuita‐Castro, Nana‐Sinkam & Ghadiali, 2012; Li et al., 2012). In this study, we further show that, while cyclic load of human articular chondrocytes in 3D culture in physiological range stimulated miR‐146a expression, mechanical overload inhibited miR‐146a expression. Such dichotomous effects of mechanical loading, which depend on its amplitude, have been observed in OA pathogenesis. While moderate exercise and weight loss have generally been shown to promote beneficial protective effects for osteoarthritic joints, altered joint loading—associated with obesity, misalignment, trauma, or joint instability—is a critical risk factor for joint degeneration (Cicuttini & Wluka, 2014). Thus, mechanical overload, such as what occur in joint cartilage during aging‐associated OA and injury‐induced PTOA, may exacerbate joint degeneration by inhibiting miR‐146a expression. Such hypothesis is supported by in vivo evidence that miR‐146a‐deficient mice exacerbate joint degeneration in both OA and PTOA in this study.

None declared.

Y. Guan and Q. Chen contributed to the conception and design of the study; acquisition, analysis, or interpretation of the data; and drafting and submission of the manuscript. Y. Guan and X. Yang performed the in situ hybridization of miR‐146a on human cartilage and DMM surgery. J. Li generated 3′UTR of Notch1 luciferase reporter plasmid and performed luciferase assay. Y. Guan, S. Du, J. Ding, and Y. Zhang performed the analysis of Western blot, immunohistochemistry, and staining, and scored the cartilage section. S. Du and Y. Gao performed X‐ray and μCT analysis. K. Yang provided the reagents and plasmid. All authors have read and approved the final submitted manuscript.




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