Cigarette smokers have a higher risk of low back pain which can be caused by disc degeneration and spinal instability. Ischemia, apoptosis, erroneous synthesis of disc macromolecules and an imbalance between matrix proteinases (MMPs) and their inhibitors (TIMPs) may be involved in the pathogenesis of disc degeneration. Along with degeneration, the disc, which by its nature has no blood vessels, becomes vascular. There is evidence that disc degeneration in cigarette smokers is more severe than in non-smokers. Cigarette smoking increases serum proteolytic activity derived from neutrophil granulocytes (white blood cells) in alveolar capillaries and by inhibiting the activity of alpha-1-antitrypsin, the most potent protease inhibitor. The authors of the original hypothesis (Fogelholm and Arho, 2001) theorized that the high serum proteolytic activity of smokers accesses a previously degenerated neovascularized disc and accelerates the degenerative process. The increased proteolytic activity can also weaken the spinal ligaments resulting in spinal instability. These processes may explain the increased risk of low back pain in cigarette smokers.
More than 15 years ago, the Department of Orthopedic Surgery, Nihon University School of Medicine, Tokyo, studied the intervertebral discs of rat models to show that smoking is a cause of intervertebral disc degeneration. A smoking chamber was developed for this study, in which 8-week-old rats underwent indirect inhalation of tobacco smoke. Each rat was forced to inhale smoke from a cigarette for an hour. The average level of nicotine in the blood of rodents exposed to cigarette smoke was approximately double that of normal human smokers. Histological and immunological studies were then conducted to evaluate the effects of smoking over different time periods. After 8 weeks, the chondrocytes (cartilage cells) in the disordered annulus fibrosus layer tended to grow larger and rounder in shape than normal chondrocytes. The level of interleukin-1beta (IL-1b) in the 8-week smoking group was significantly higher than in the control group. The inhalation of tobacco smoke had therefore increased the local production and release of inflammatory cytokines and the consequent decomposition of cartilage activity.
The molecular mechanism of intervertebral disc degeneration has been studied mainly in vitro but little in vivo and gene expression analysis has been performed in some studies. A team of researchers implanted a pump filled with a diluted nicotine solution under the skin of rabbits in the laboratory and held it for 8 weeks. This model was designed to maintain the nicotine concentration in the blood at approximately 110 ng / mL. Saline treated rabbits were used as control animals. Nicotine treatment resulted in necrosis and hyalinization (clearing) of the nucleus pulposus in all rabbits. The annulus fibrosus showed a disturbance in the layered arrangement of its laminae. This resulted in changes indicative of shrinkage of the vascular buds and calcification around the blood vessels. Nicotine treatment resulted in hypertrophy of the vascular walls, necrosis in endothelial cells and narrowing of the vascular lumen. This resulted in the delineation of vascular buds (neo-angiogenesis) near the vertebral endplate and a reduction in their number.
Another team of researchers used a smoke chamber to create a rat model of intervertebral disc degeneration induced by secondhand cigarette smoke. The study sought to determine the molecular changes in the degeneration of the intervertebral discs of rats induced by passive cigarette smoking. The goal was to quantify and compare the levels of gene expression in the discs of rats inhaling secondhand smoke and unexposed rats. After total RNA extraction from intervertebral discs of rats reared in a smoking chamber for 2 to 7 weeks. The corresponding cDNA was synthesized, and quantitative analysis of gene expression was performed by real-time PCR. Disc samples were also subjected to histological examination. Histological changes of the nucleus pulposus and annulus fibrosus were detected after 2 weeks of smoking and became ubiquitous after 7 weeks. The presence of collagen was significantly lowered after 7 weeks of secondhand smoke. No significant increase in metalloproteinase 3 expression was observed, but aggrecan (proteoglycan) and TIMP-1 inhibitor expression began to increase at 4 weeks of smoking.
The latest scientific evidence suggests the harmful roles of cellular senescence (aging) in the pathogenesis of intervertebral disc degeneration. The senescence of the senescent disc cells reduces the number of still young functional cells. Furthermore, the cells of the senescent disc could accelerate the degeneration process through their aberrant effects with which the senescent cells cause the senescence of neighboring cells. In practice, the aged cells of the disc would act as a trigger for the aging of the surrounding cells, accelerating the catabolism of the matrix and inflammation. Therefore, anti-senescence has been proposed as a new therapeutic target for disc degeneration. However, the development of anti-senescence therapy relies on understanding the molecular mechanism of disc cell senescence. It is therefore necessary to investigate the cellular responses that occur as aging progresses. There is already evidence, however, that during the disc degeneration process, the damage activated both the p53-p21-Rb and p16-Rb pathways to induce senescence of the disc cells.
Meanwhile, disc cell senescence appears to be regulated by multiple cell signaling pathways, suggesting the complex regulatory network of disc cell senescence. Much knowledge is available on the role of oxidative stress, inflammatory cytokines in cartilages in knee osteoarthritis models, especially the role of IL-1 and TNF-alpha cytokines. Likewise, there is a lot of laboratory knowledge and from experiments on biopsies of patients on the degenerative role of free radicals (lipoperoxides and nitrogen oxides), at the level of cartilage cells obtained from patients with knee osteoarthritis or rheumatoid arthritis. Oxidative stress is a recognized component in cellular aging in general, as it is also involved in the physio-pathological process of many clinical conditions. Given the large numbers that populate clinical rheumatology practice, understanding the mechanism of disc cell senescence contributes best to the development of anti-aging therapies against spinal cartilage degeneration.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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