l‐tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways

Abstract

Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)‐activated NF‐κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l‐tetrahydropalmatine (l‐THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l‐THP inhibited osteoclastic differentiation at the early stage, down‐regulated transcription level of osteoclastogenesis‐related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l‐THP inhibited the phosphorylation of P50, P65, IκB, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF‐κB was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co‐immunoprecipitation indicated that l‐THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l‐THP significantly inhibited ovariectomy‐induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l‐THP suppressed osteoclastogenesis by blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways. l‐THP is a promising agent for treating osteoclastogenesis‐related diseases such as post‐menopausal osteoporosis.

A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine

“…In addition, THP activates the K ATP channel and plays a role in vascular relaxation, and promotes angiogenesis by regulating the sequence of citrulline-to-arginine flux, arginine biosynthesis, and VEGFR2 expression in endothelial cells ( Cui et al, 2021 ), as shown in Figure 6 . Furthermore, THP can inhibit osteoclast formation in a dose-dependent manner and has no cytotoxicity at a concentration lower than 19.00 μg/ml ( Zhi X. et al, 2020 ). In vitro experiments, THP suppressed early osteoclast differentiation, downregulated the transcription level of osteoclast-related genes, and impaired the function of osteoclasts in bone marrow monocytes cells and mouse leukemic monocyte/macrophage cell line RAW264.7 cells.…”

Gujin Dan is a Chinese medicine formulation that stimulates cell proliferation and differentiation by controlling multiple genes involved in MC3T3-E1 cells

“…Paeoni orin treatment of osteoporosis can be divided into two general directions: inhibiting osteoclast activity [70] and improving osteoblast activity [71,72], It slows bone resorption by inhibiting osteoclast activity and promotes bone formation by increasing osteoblast activity. Corydalis Yanhusuo contains Tetrahydropalmatine, Experimental studies in vivo and in vitro have shown that Tetrahydropalmatine inhibits osteoclast formation by inhibiting NF-κB and MAPK pathways [73]. Coicis Semen extract has been shown to promote osteoblast proliferation and effectively relieve osteoporosis in animals [73][74][75].…”

A Comparison of the Risk of Fracture in Rheumatoid Arthritis Patients with and without Receiving Chinese Herbal Medicine

“…A recent study showed that l-tetrahydropalmatine, a major compound purified from this formula, significantly suppresses the receptor activator of nuclear factor κB ligand (RANKL)-activated NF-κB and MAPK pathway. 24 This pathway involves the inhibition of osteoclastogenesis and regulation of osteoblast differentiation and osteogenic formation. 25 The present study also showed that use of Bei-Mu and Da-Huang may lessen the risk of fracture among RA subjects.…”