Leptin and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain—an in vitro study in a bovine model

Abstract

The aim of this study was to identify the effects of leptin upon the intervertebral disc (IVD) and to determine whether these responses are potentiated within an environment of existing degeneration. Obesity is a significant risk factor for low back pain (LBP) and IVD degeneration. Adipokines, such as leptin, are novel cytokines produced primarily by adipose tissue and have been implicated in degradative and inflammatory processes. Obese individuals are known to have higher concentrations of serum leptin, and IVD cells express leptin receptors. We hypothesise that adipokines, such as leptin, mediate a biochemical link between obesity, IVD degeneration and LBP. Methods The bovine intervertebral disc was used as a model system to investigate the biochemical effects of obesity, mediated by leptin, upon the intervertebral disc. Freshly isolated cells, embedded in 3D alginate beads, were subsequently cultured under varying concentrations of leptin, alone or together with the pro-inflammatory cytokines TNF-α, IL-1β or IL-6. Responses in relation to production of nitric oxide, lactate, glycosaminoglycans and expression of anabolic and catabolic genes were analysed. Results Leptin influenced the cellular metabolism leading particularly to greater production of proteases and NO. Addition of leptin to an inflammatory environment demonstrated a marked deleterious synergistic effect with greater production of NO, MMPs and potentiation of pro-inflammatory cytokine production. Conclusions Leptin can initiate processes involved in IVD degeneration. This effect is potentiated in an environment of existing degeneration and inflammation. Hence, a biochemical mechanism may underlie the link between obesity, intervertebral disc degeneration and low back pain. Graphical abstract These slides can be retrieved under Electronic Supplementary Material.

Molecular Relationships among Obesity, Inflammation and Intervertebral Disc Degeneration: Are Adipokines the Common Link?

“…However, there are some contradictory data reporting that cumulative or repetitive loading associated with higher body mass have no deleterious action on IVD [29]. This suggests that beyond mechanical effects, obesity could exert metabolic and/or inflammatory effects that contribute to IVDD development [30,31].…”

“…Analyzing the effects of leptin in disc cells proteome, recently, Segar and colleagues demonstrated that this adipokine, alone or in synergy with TNF-α, IL-1β, or IL-6, significantly increases nitric oxide production, and the expression of pro-inflammatory cytokines (TNF-α and IL-6), and MMPs (MMP-3, -7, -9, and -11, as well as ADAMTS -4, and -5) [31]. These data indicated that leptin can initiate degradative and inflammatory cascades in disc cells, being its deleterious effects potentiated by an existing inflammatory environment [31]. Similar effects were previously verified by Miao et al in rat NP cells [40].…”

Chemerin facilitates intervertebral disc degeneration via TLR4 and CMKLR1 and activation of NF-kB signaling pathway

“…However, adipokines have been reported to play major roles in the systemic diseases [15][16][17], including arthritis, and disc degeneration, known as the most common orthopedic disease [18][19][20][21]. According to data, leptin and resistin accelerated disc degeneration by inducing inflammation, and then substrate degradation [22][23][24]. No study has reported about the role of chemerin in intervertebral disc, so the objective of our study was to explore the relationship between chemerin, intervertebral disc, inflammation, and matrix degradation.…”

Articular Repair/Regeneration in Healthy and Inflammatory Conditions: From Advanced In Vitro to In Vivo Models

“…It was shown that the addition of leptin can initiate and potentiate (when combined with TNF-α, IL-1β, or IL-6) the production of molecules involved in IVD degeneration and back pain, namely, MMPs and NO. [110] As described for articular cartilage in the previous section, one of the current trends in regenerative medicine, in vitro, is the use of decellularized matrices as 3D support material. This native tissue provides the unique ECM composition and Biomaterial-based culture HMw-HA hydrogels with NP cells HA hydrogel suppressed the expression of the inflammatory receptors IL-1R1 and My D88 and downregulated the expression of NGF and BDNF.…”