Abstract
Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD). Here we present evidence from miRNA microarray analyses of clinical data sets along with in vitro and in vivo experiments that miR-141 is a key regulator of IDD. Gain- and loss-of-function studies show that miR-141 drives IDD by inducing nucleus pulposus (NP) apoptosis. Furthermore, miR-141 KO in mice attenuated spontaneous and surgically induced IDD. Mechanistically, miR-141 promotes IDD development by targeting and depleting SIRT1, a negative regulator of NF-κB pathway. Therapeutically, upregulation or downregulation of miR-141 by nanoparticle delivery in IDD model aggravated or alleviated experimental IDD, respectively. Our findings reveal a novel mechanism by which miR-141, in part, promotes IDD progression by interacting with SIRT1/NF-κB pathway. Blockade of miR-141 in vivo may serve as a potential therapeutic approach in the treatment of IDD.
Highlights
Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD)
Numerous potential causes are recognized, the disorder is strongly associated with intervertebral disc degeneration (IDD), which accounts for approximately 40% of all Low back pain (LBP) cases[2]
There is increasing evidence supporting the role of microRNAs in the processes that leads to IDD10–12. miRNAs are a class of non-coding RNA molecules that play a central part in cell differentiation, proliferation, and survival by binding to complementary target mRNAs, resulting in mRNA translational inhibition or degradation[13]
Summary
Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD). We present evidence from miRNA microarray analyses of clinical data sets along with in vitro and in vivo experiments that miR-141 is a key regulator of IDD. MiR-141 promotes IDD development by targeting and depleting SIRT1, a negative regulator of NF-κB pathway. An enhanced understanding the molecular mechanisms underlying this imbalance has the potential to identify new therapeutic targets for IDD. Establishment of a miRNA expression profile is important for investigating the underlying functional mechanisms for IDD, and a better knowledge of their expression patterns could reveal molecular signatures that can be developed as therapeutic targets as well. MiR-141 level are associated with grade of disc degeneration These data collectively indicate that miR-141 could be a target for therapeutic intervention against IDD
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