Table 2.

Therapeutic approaches to regulate JAK2/STAT3 in OA

Classification	Name	Effect on JAK2/STAT3	Mechanism	Consequence	References
MicroRNAs	MiR-375 inhibition	activation	ADAMTS-5↓, MMP-13↓, COL-II↑, AGG↑, p-JAK2/JAK2↑, p-STAT3/STAT3↑, Bcl-2/Bax↑	Improved the ability of chondrocytes to antagonize oxidative stress and maintain ECM homeostasis	[28, 67]
	MiR-149-5p	Inhibition	AGT↓, ANGII, AT1R	Regulated and combined AGT, promoted the inflammatory responses induced by IL-6	[39]
	MiR-216a-5p	Inhibition	Bax↓, Caspase-3↓, Bcl-2↑	Promoted the proliferation and migrations well as inhibited apoptosis in chondrocytes	[29]
	MiR-224-5p	Inhibition	MMP-9↓, MMP-13↓, COL-II↑, AGG↑, Caspase-3↓, Circ_PDE1C↓	Inhibited chondrocytes apoptosis and ECM degradation. Targeted CCL2 and accelerated cartilage degradation	[44]
Traditional Chinese medicine	Danshen	activation	P-JAK2, p-STAT3↓, GSH, SOD, CAT↑, Bcl-2↑, Bax, caspase3, PARP↓	Attenuated cartilage injuries by activating JAK2/STAT3 pathway	[71]
	Diosgenin	activation	P-JAK2, p-STAT3, SDH, COX, SOD↑, Bax↓	Protected OA cartilage cells by activating the JAK2/STAT3 pathway, which effectively reduces mitochondrial oxidative stress damage and apoptosis in OA cells during the pathological process	[73]
	curcumin	activation	P-JAK2, p-STAT3,	Increased the mitochondrial resistance to oxidative stress in chondrocytes, significantly slows down the degeneration of articular cartilage, and reduces the level of OA progression	[75]
	Resveratrol	Inhibition	JAK2, STAT3, SOCS3, MMP-13↓	No significant leptin resistance existed in articular cartilage of obesity-related OA and the inhibitory effect of RES on obesity-related OA via alleviating JAK2/STAT3 signaling pathway	[77]
Inhibitors	AG490	Inhibition	JAK2↓	Inhibited JAK2/STAT3 activation and apoptosis in chondrocytes induced by IL-1β	[62, 79]
	WP1066	Inhibition	JAK2, STAT3↓	Downregulated the expression of JAK2/STAT3 to suppress the chondrocytic inflammation responses induced by IL-6	[39]
	Tofacitinibis	Inhibition	JAK, STAT3↓	Moderated chondrogenic hypertrophy in human chondrocyte lines via downregulation of JAK/STAT3	[68]
	Pranlukast	Inhibition	JAK2, STAT1↓	Reversed the enhancement levels of pro-inflammatory cytokines to prevent the progression of OA	[81]
	STA21	Inhibition	STAT3↓	Blocked STAT3 dimerization and DNA binding to alleviate joint pain and cartilage damage	[82]
	Stattic	Inhibition	STAT3↓	Reduced the severity of OA cartilage lesions and decreased the size of osteophytes. Stattic had no significant effect on the synovium or the subchondral bone	[55]