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  • Activation of the Beta-Catenin-mediated CTGF Secretory Pathway via TGF-Beta in Senescent Chondrocytes is a Mechanism for Intervertebral Disc Degeneration

    Final Number:

    Nitesh Patel; Qiuqian Wu; Jason H. Huang MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2018 Annual Meeting

    Introduction: Intervertebral disc degeneration is an age-related process that begins during childhood. Regions of discs containing chondrocyte-like cells are prone to degenerate, but the mechanism is unknown. Overexpression of Smurf2 under the control of type II collagen alpha 1 (Col2a1) promoter has been shown to accelerate age-related intervertebral disc degeneration in Col2a1-Smurf2 transgenic mice. Notably, increased levels of connective tissue growth factor (CTGF) protein and TGF-beta mRNA have been observed in chondrocyte-like cells in Col2a1-Smurf2 transgenic mice discs, implicating CTGF in disc degeneration progression. This study aimed to elucidate the mechanism by which Smurf2 overexpression in chondrocyte-like cells results in increased CTGF secretion during disc degeneration in Col2a1-Smurf2 transgenic mice.

    Methods: Primary old bovine nucleus pulposus (NP) cells were isolated from 3.5-year-old caudal bovine intervertebral discs as substitutes for chondrocyte-like cells in Col2a1-Smurf2 transgenic mice discs. Primary young bovine NP cells were isolated from 3-month-old caudal bovine intervertebral discs to represent normal cells in wild-type mice discs. The cells were transfected with lentiviruses expressing Smurf2 and GFP. Western blot, immunoprecipitation, and immunohistochemistry were utilized to analyze the downstream effects of TGF-beta treatment on beta-catenin and CTGF in the old bovine NP cells, young bovine NP cells, and young bovine NP cells after gain of Smurf2 function.

    Results: The primary old bovine NP cells were found to be in various stages of senescence. Treatment of these cells with TGF-beta induced rapid accumulation of cytoplasmic beta-catenin, which interacted with CTGF and recruited it to the plasma membrane for secretion. This TGF-beta-initiated, beta-catenin–mediated CTGF secretory cascade did not occur in primary young bovine NP cells; however, the cells became senescent after Smurf2 overexpression, thereby allowing the cascade to occur.

    Conclusions: Smurf2-induced intervertebral disc degeneration in Col2a1-Smurf2 transgenic mice occurs through activation of the CTGF secretory pathway in senescent chondrocyte-like cells within intervertebral discs.

    Patient Care: Intervertebral disc degeneration is a major cause of back pain, especially in the lumbar region. Understanding the molecular mechanism of disc degeneration can help guide the development of an effective treatment, which is particularly important given that disc degeneration is currently inevitable with aging.

    Learning Objectives: After reading this poster, participants should be able to: 1. Describe the basic pathophysiology of intervertebral disc degeneration. 2. Discuss the potential molecular mechanisms by which intervertebral disc degeneration is mediated.


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