# Effects of Epigallocatechin-3-O-Gallate on Bone Health
## 3 Biochemical Effects of EGCG
### Inhibition of Interleukin-6 Synthesis  
Cytokines are short-lived proteins with a low molecular mass of approximately 15-20 kDa and play crucial roles in autocrine, paracrine, and endocrine signalling. These molecules play a key role in the development and activity of the immune system. Interleukin-6 (IL-6) family cytokines are classified based on the common signalling receptor subunit glycoprotein 130 kDa (gp130). Currently, this class includes eight cytokines: IL-6, IL-11, ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin-like cytokine (CLC), cardiotrophin 1 (CT-1), and IL-27 [108]. These cytokines demonstrate unique cell-surface expression by interacting with the specific transmembrane IL-6 receptor (mIL-6R) or its soluble forms (sIL-6R) and the signal-transducing subunit molecule gp130 [109]. In the case of the treatment of different autoimmune diseases, suppressing the IL-6 family of cytokines becomes advantageous. Furthermore, recent advances in cytokine blocking have helped reduce adverse effects related to metabolic dysfunction and bacterial infections [108].  
Regarding interleukin-6, the presence of both anti-inflammatory and pro-inflammatory activity is induced by different biological mechanisms and sources [110]. It is well known that interferon-\(\beta\)2 (IFN-\(\beta\)2), hepatocyte-stimulating factor, and hybridoma/plasmacytoma growth factor (also known as IL-6) are mainly produced by monocytes and macrophage cells [111]. Moreover, B and T cells, hepatocytes, endothelial cells, fibroblasts, keratinocytes, mesangial cells, adipocytes, and several tumour cells can produce IL-6 constitutively or after stimulation [109; 110; 112]. IL-6 plays a significant role in the proliferation and differentiation of cells in humans. Additionally, the immunopathogenic role of IL-6 in tumour development, metastasis, angiogenesis, apoptosis, and therapeutic resistance has been proven in recent publications [109; 113; 114; 115]. It also exerts a significant physiological effect on a wide range of functions, such as promoting B cell differentiation [58]. When osteoblasts are affected by IL-1 or IL-6, the expression of RANKL, an osteoclast differentiation factor, is induced, resulting in bone resorption [116; 117; 118].  
According to [PERSON] et al. [111], triggering the trans-signalling mechanism with IL-6 promotes various pathological pathways, including those that could contribute to multiple sclerosis, rheumatoid arthritis, anaemia, inflammatory bowel disease, [PERSON]'s disease, Alzheimer's disease, and cancer. Among these routes are JAK/STAT3, Ras/MAPK, and PI3K-PKB/Akt, and the regulation of CD4+ T cells and VEGF levels. The research of [PERSON] et al. [117] provided an example of tocilizumab, an IL-6 receptor (IL-6R)-neutralising monoclonal antibody. It was approved in more than 100 countries for the treatment of autoimmune diseases induced by IL-6. Additionally, patients with rheumatoid arthritis demonstrated that a blockade of IL-6 activity was observed to be at least as efficient as the blockade of the tumour necrosis factor [117]. Normally, an average person's buffer of IL-6 in the blood is in the range of 1-5 pg/mL. The concentration of cytokines rapidly increases several thousand times during inflammatory states, and under lethal septic stages, it can even reach levels of several mg/mL. Soluble sIL-6R concentration usually stays within 40-75 ng/mL, and the levels of ssp130 reach approximately 250-400 ng/mL [108]. In NRG cells, suppressing the production of interleukin 6 and RANKL by EGCG led to the inhibition of inflammation in osteomyelitisitis treatment [54]. The reduction of IL-6 synthesis by EGCG on osteoblast-like MC3T3-E1 cells is caused by different mechanisms, such as the attenuation of the p44/p42 MAP kinase pathway and/or p38 MAP kinase [58; 59], as well as the inhibition of the PDGF-BB-induced phosphorylation of SAPK/JNK [57].