Theaflavin-3,3′-Digallate Promotes the Formation of Osteoblasts Under Inflammatory Environment and Increases the Bone Mass of Ovariectomized Mice

Abstract

Postmenopausal osteoporosis is a disease of bone mass reduction and structural changes due to estrogen deficiency, which can eventually lead to increased pain and fracture risk. Chronic inflammatory microenvironment leading to the decreased activation of osteoblasts and inhibition of bone formation is an important pathological factor that leads to osteoporosis. Theaflavin-3,3′-digallate (TFDG) is an extract of black tea, which has potential anti-inflammatory and antiviral effects. In our study, we found that TFDG significantly increased the bone mass of ovariectomized (OVX) mice by micro-CT analysis. Compared with OVX mice, TFDG reduced the release of proinflammatory cytokines and increased the expression of osteogenic markers in vivo. In vitro experiments demonstrated that TFDG could promote the formation of osteoblasts in inflammatory environment and enhance their mineralization ability. In this process, TFDG activated MAPK, Wnt/β-Catenin and BMP/Smad signaling pathways inhibited by TNF-α, and then promoted the transcription of osteogenic related factors including Runx2 and Osterix, promoting the differentiation and maturation of osteoblasts eventually. In general, our study confirmed that TFDG was able to promote osteoblast differentiation under inflammatory environment, enhance its mineralization ability, and ultimately increase bone mass in ovariectomized mice. These results suggested that TFDG might have the potential to be a more effective treatment of postmenopausal osteoporosis.

Potential mechanism of tea for treating osteoporosis, osteoarthritis, and rheumatoid arthritis

“…Theaflavin-3,3′-digallate activates several signaling pathways, including the tumor necrosis factor-α (TNF-α)-inhibited mitogen-activated protein kinase (MAPK), Wnt/βcatenin, and BMP/Smad pathways. This mechanism ultimately promotes the transcription of osteogenesis-associated factors such as RUNX2 and Osterix, leading to osteoblast differentiation and maturation (46). Furthermore, various tea extracts and tea polyphenols inhibit osteoclast formation, with EGCG being the most effective (47)(48)(49)(50)(51).…”

The potential application of fermented tea as a drink for regulating bone mass

“…In vitro experiments have shown that TFDG can promote the formation of osteoblasts in an inflammatory environment and enhance their mineralization ability. During this process, TFDG activates the MAPK, Wnt/beta-Catenin, and BMP/Smad signaling pathways ( Ge et al, 2021 ). Hou found that TF3 can effectively inhibit the expression of pro-inflammatory cytokines in ovariectomized mice, promote polarization of M1 macrophages to M2 macrophages, reduce inflammatory response, promote bone formation, and effectively reduce bone loss.…”

Oxidative Stress and Natural Antioxidants in Osteoporosis: Novel Preventive and Therapeutic Approaches

“…Furthermore, green tea extract in the condition of oxidative stress led to the increased expression of osteocalcin and collagen 1α1 during osteoblast differentiation [148]. In addition to green tea, black tea polyphenols, particularly theaflavin-3,3 -digallate (TFDG), were recently found through in vitro and in vivo studies [149][150][151] to display strong antioxidant and anti-inflammatory activities by reducing the levels of nitric oxide precursor, malondialdehyde (MDA), lipid peroxidation, and SOD. Furthermore, the same studies showed that serum levels of TNFα, IL-6, and RANKL were reduced, along with tartrate-resistant acid phosphatase activity, the osteoclast enzyme.…”