# Effects of Epigallocatechin-3-O-Gallate on Bone Health
## 2 Functional Effects of EGCG  
EGCG can exert various functional effects as illustrated in Figure 1. Most of these are positive, although a few adverse ones have also been reported. EGCG supplementation has been demonstrated to influence various aspects of bone formation and maintenance in both in vitro and animal trials. One of its positives is the upregulation of alkaline phosphatase (ALP), which stimulates bone mineralisation [26]. Additionally, EGCG has been shown to modulate osteoblast function by selectively inhibiting the extracellular signal-regulated kinase (ERK; p42/p44) branch of the mitogen-activated protein kinase (MAPK) pathway, thereby reducing PGD2-induced HSP27 expression in osteoblasts. This process may influence cellular stress responses rather than directly promote osteoblast proliferation or differentiation [27]. EGCG has also shown the potential to induce bone regeneration through mechanisms such as enhancing bone callus formation and by modulating the collagen membrane structure and function [21]. However, in certain cases, EGCG supplementation may require co-administration with \(\alpha\)-calcium triphosphate to effectively promote the regeneration [28]. Furthermore, the concentration levels of EGCG play a crucial role in how effective it is. High dosages of EGCG can inhibit the proliferation of mesenchymal cells involved in osteogenesis in periodontitis, while intermediate concentrations can promote it. It has been shown that an intermediate dose of 4 and 6 \(\upmu\)M promotes human periodontal ligament cell (hPDLC) osteogenesis by increasing ALP activity and the mRNA and protein expression levels of the osteogenic markers type I collagen (COLI), runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and Osterix (OSX). Specifically, quantitative real-time PCR analysis demonstrated that EGCG treatment significantly upregulated the mRNA levels of COLI, RUNX2, OPN, and OSX, indicating enhanced osteogenic differentiation at these concentrations [29]. Yet another study proved that the therapeutic effects of EGCG are dose-dependent. [PERSON] et al. conducted research in which immunodeficient mice were transplanted in vivo with human alveolar bone-derived cells (hABCs) that had been pretreated with 10 \(\upmu\)M of EGCG and mixed with calcium phosphate carrier combined with EGCG (0.1, 0.5, or 1.5 mg) [30]. The results indicated that EGCG up to 10 \(\upmu\)M slightly increased osteogenic differentiation, while at higher concentrations above 25 \(\upmu\)M, the proliferation and migration of hABCs were reduced. Hard tissue formation efficiency was enhanced when the low concentration in the 0.1 mg EGCG group was used, whereas EGCG levels exceeding 0.5 mg significantly reduced hard tissue formation. Figure 1: Various functional effects of EGCG on bone health. In some instances, such as human bone marrow mesenchymal stem cells (hBM-MSCs) and human mesenchymal stem cells (hMSCs), additional osteoinductive agents or mechanical stretching were found to induce this effect by increasing the osteogenic differentiation of MSCs and accelerating osteogenic differentiation, respectively [31; 32]. Notably, EGCG prevents the TNF-\(\alpha\)-mediated inhibition of osteogenic differentiation in hBM-MSCs while concurrently modulating osteoinmunological pathways. It suppresses TNF-\(\alpha\)-induced IL-6 synthesis in osteoblasts via the attenuation of p44/p42 MAP kinase and stress-activated protein kinases/Jun amino-terminal kinases (SAPK/JNK) pathways, thereby reducing RANKL expression and shifting the RANKL/OPG balance towards bone formation [33]. EGCG does not solely impact tissue formation but contributes to improving bone microarchitecture and preventing bone loss [34; 35]. [PERSON] et al. proved that this molecule hampers bone resorption by inducing apoptosis in osteoclast cells [36]. Interestingly, one study suggested that bone resorption might be stopped by the combined actions of osteoblasts and osteoclasts, without involving apoptosis [37].