Table 2.

The anti-inflammatory effects and mechanisms of rhein on various arthritis

Types of arthritis	Characteristics	Mechanisms	References
Osteoarthritis (OA)	Degenerative lesions of articular cartilage	Rhein inhibits LPS-induced IL-1β production by synovial tissue and cartilage, and reverses the inhibitory effect of LPS on cartilage35S uptake	[58]
		Rhein suppresses the interleukin-1b converting enzyme(ICE), blocks matrix metalloproteinase 3(MMP-3) synthesis, and increases the production of prostaglandin E2 (PGE2)	[7]
Rheumatoid arthritis (RA)	Inflammatory synovitis and progressive joint lesions	Rhein could block the ATP-induced [Ca2+]c increases in a dose-dependent manner. Besides, rhein could also suppress the production of intracellular reactive oxygen species (ROS) induced by ATP in synoviocytes that was resulted from P2X4-mediated Ca2+ entry	[61]
		Rhein can effectively inhibit the IL-1-activated MAPK pathway and the binding of NF-κB and AP-1 transcription factors. In addition, rhein can reduce the procatabolic effect of the cytokine, by reducing the MMP1 synthesis, and enhance the synthesis of matrix components	[62]
		Rhein reduces VEGF and hippocampal tissue hypoxia-inducible factor-1α (HIF-1α), and also inhibits the up regulation of MMP-13	[63]
Gouty arthritis(GA)	Hyperuricemia and urate crystal-induced inflammation	Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1β, TNF-α and caspase-1 protease in urate crystal-activated macrophages	[26]
		Rhein could inhibit the xanthine oxidase(XOD) activity	[69]
Other arthropathies	Bone resorption in osteoclast	Rhein was validated for its inhibitory effects on the formation of TRAP-positive multinucleated cells and bone resorption	[70]
		Rhein dose-dependently and statistically inhibited osteocalcin release, a situation explained by a reduction of mRNA levels for osteocalcin	[71]