Inhibition of TNF-alpha Signaling to Reduce Intervertebral Disc Inflammation

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Abstract Chronic back pain related to intervertebral disc (IVD) degeneration is a significant problem, costing billions in the U.S. alone. Our proposal will explore new aspects of the factors that lead to disc degeneration and inflammation, thus accelerating research on IVD degeneration and related back pain. The TNF-α-induced protein-8 (TNFAIP8, known as TIPE) family consists of four members (TNFAIP8 and TIPE1-3). They are novel cytoplasmic proteins recently found to be key factors regulating inflammation. Our preliminary data have shown that TNFAIP8 family proteins regulate macrophage infiltration into the injured IVD. The premise of our proposal is that TNFAIP8 family members may be key regulators in IVD inflammation, and that a novel small molecule inhibitor of tumor necrosis factor receptor (TNFR)-1 could represent a therapeutic tool to reduce inflammation. In Aim 1, we hypothesize that genetic inactivation of TNFAIP8/TIPE2 results in reduced inflammation in the injured mouse tail IVD. We will determine if genetic inactivation of TNFAIP8/TIPE2 will ameliorate IVD inflammation and degeneration. We have acquired and are currently maintaining colonies of mutant mice lacking two members of the TNFAIP8 family (TNFAIP8-/-, TIPE2-/-, and TNFAIP8/TIPE2 double knockout). Mouse tail IVDs will be challenged with a needle puncture injury. Changes in macrophage infiltration and cytokine gene expression post-injury will be compared among the mutant mice and with their wild type littermate controls. In Aim 2, we further hypothesize that a novel small molecule inhibitor of TNFR1 (SGT11) could represent a therapeutic tool to reduce inflammation. Small molecules are especially attractive since they could be modified for oral drug delivery. SGT11 has been shown to inhibit inflammation by changing the conformation of TNFR1. Unlike current anti-TNF therapy that inhibits both TNFR1 and TNFR2 activation, SGT11 inhibits TNFR1 but not TNFR2. If successful, this will be the first small molecule to modulate IVD inflammation. We will determine if SGT11 could ameliorate IVD inflammation and reduce TNFAIP8/TIPE2 expression in the wild-type mouse. Mouse tail IVDs will be punctured with a needle, with or without SGT11 treatment. Changes in macrophage infiltration, cytokine and TNFAIP8 family gene expression in the IVD will be compared between SGT11-treated and control groups. The proposed exploratory study breaks ground toward a novel direction since modulating TNF-TNFAIP8 axia with genetic methods and small molecule inhibitors has not been previously studied in the IVD. Discovery of drugs that modulate IVD inflammation would result in a paradigm shift from current invasive surgeries on late stage disease to early noninvasive therapies, thus benefiting patients.