Estrogen reverses nicotine‐induced inflammation in chondrocytes via reducing the degradation of ECM

Abstract

Problem: Osteoarthritis (OA) is a chronic disease with a very high incidence and the pathology of which is quite complex. Epidemiological investigation showed that OA may be related to smoking and estrogen levels, but there are few studies focused on the cross-effect of these two factors. This research aims to investigate the molecular mechanism of nicotine and estrogen effects on chondrocytes to study the effect of smoking on the incidence of osteoarthritis in women. Method of the study:Nicotine was added to obtain inflammatory supernatants of macrophages, which were used to induce chondrocyte inflammation. Toluidine staining and immunohistochemistry were used to detect the extracellular matrix (ECM) of chondrocytes, while the important proteins in the metabolism of chondrocytes were detected by Western blot. Results: Nicotine-induced inflammatory supernatant promoted the degradation of ECM, such as type II collagen, aggrecan and proteoglycan 4. While in the presence of physiological concentrations of estrogen, this destructive effect is reversed. On the molecular level, estrogen (17β-estradiol, 1 nmol/L) can inhibit the matrix degrading enzymes and promote the transforming growth factor (TGF)-β1 pathway which is involved in matrix synthesis. However, in the presence of inflammatory induction, although estrogen could still inhibit the expression of matrix degrading enzymes, it inhibited the TGF-β1 pathway. Moreover, the different inflammatory factors in the inflammatory supernatant, mainly tumor necrosis factor-α, interleukin-1β, had different effects on the metabolic processes of chondrocytes. Conclusion: Estrogen reverses nicotine-induced inflammation mainly via reducing the degradation of ECM. The cross-effect of estrogen and inflammatory factor inhibitors can be a potential clinical reference for OA patients. K E Y W O R D S chondrocytes, estrogen, extracellular matrix, nicotine, osteoarthritis | INTRODUC TI ONOsteoarthritis (OA) is one of the most common chronic, degenerative joint inflammations which can worldwide cause severe disabilities. 1 The pathology of this disease is very complex. Previous studies have found that estrogen is an important influencing factor that can inhibit the development of OA. 2 Recent studies also show that smoking has a certain impact on the occurrence of OA, but the specific mechanism is controversial. 3

Tamoxifen Inhibits the Progression of Trauma-Induced Heterotopic Ossification in Mice

“…As the activity of ERa was stimulated by tamoxifen in mice, the expression of p-Smad2/3 (which are downstream transcription factors of TGF-b signaling pathway and essential in the progression of acquired and congenital HO) was decreased in a dose-dependent response to tamoxifen, following the overactive TGF-b signaling which was interrupted in the inflammation and chondrogenesis phases and subsequently the ectopic bone formation was retarded. This cross-regulation between ERa and TGF-b is consistent with a recent study of Peng et al [42]. It showed that estrogen has a potential inhibitory effect on TGF-b1 signaling pathway by reducing the expression of Smad2/3 after inflammation.…”

Evaluation of the effects of nicotine on the friction of the articular cartilage and the reversion of the estrogen in vitro

“…The estrogen was used to and the friction on the cell was measured. The μ and PRG4 content were both recovered a lot which indicates the protective effect of the estrogen on the lubrication as verified in this study and previously (Peng et al, 2019). There are seldom reports to state relation between estrogen and friction of the articular cartilage, though, the positive effect of the estrogen were studied through different pathway.…”

“…These results may be attributed to the expression levels of lubricants on the surface of the articular cartilage as evidenced by the immunohistochemistry results. After nicotine treatment, The level of inflammatory factors(TNF-α, IL-1β) was detected in our previous work (Peng et al, 2019). The increase in μ after nicotine treatment indicates a loss of the boundary lubricant, with PGR4 as the strongest candidate.…”

“…The secretome analysis of human articular chondrocytes suggested a negative effect of nicotine on the joint (Lourido et al, 2016). Our previous study showed that the nicotine can induce inflammation on articular cartilage (Peng et al, 2019). On the other hand, the effects of nicotine on the joint and the mechanisms involved in cartilage degradation remains controversial (Turner et al, 1997).…”

Psoralen downregulates osteoarthritis chondrocyte inflammation via an estrogen-like effect and attenuates osteoarthritis

“…Studies have shown that the decline in the level of estrogen in the body is closely related to the occurrence and severity of OA [ 3 ]. Studies have indicated that estrogen can reverse the degradation of the extracellular matrix caused by inflammation in chondrocytes [ 4 ]. Therefore, we believe that estrogen supplementation can alleviate the progression of OA.…”