Table 2.

Promising therapeutic roles of MDSCs in bone-related diseases

Diseases	Potential therapeutic strategies	Mechanisms	References
Bone metastasis	Block the positive effect of MDSCs on primary tumor	MDSCs play as a contributor to primary tumor in angiogenesis, drug resistance, anti-tumor immunity, etc.	[5, 14, 17–31]
	Inhibition of MDSCs in the process of bone metastasis	MDSCs are widely involved in bone metastasis processes such as EMT and PMN formation	[39–41, 48–53]
	Target MDSCs in the bone microenvironment to block vicious cycle	MDSCs promote osteoclastogenesis indirectly or directly	[71–79]
	Increase the cell death rate of MDSCs to disrupt homeostasis of MDSCs	MDSCs accumulation is a balance of MDSCs differentiation and MDSCs death	[151–161]
Osteosarcoma	Regulate the metabolism of MDSCs	Met inhibits OS growth based on metabolic regulation of MDSCs	[166]
	Induce the apoptosis of MDSCs	Infiltrating MDSCs were CXCR4 positive, and the binding of CXCR4 to SDF-1 could reduce the apoptosis of MDSCs	[167]
	Supplement classical immunotherapy	Many drugs that inhibit MDSCs function enhance anti-PD-1 antibody immunotherapy, such as AMD3100, SNA	[167, 168]
	Prevent MDSCs migration	IL-18 could induce MDSCs to migrate into the OS tissue	[169]
	Eliminate MDSCs	Neoadjuvant chemotherapy and ATRA treatment could reduce the quantity of M-MDSCs to treat OS	[170, 171]
Rheumatoid arthritis	Suppress the positive effect of MDSCs on Th17 cells	MDSCs enhance Th17 cells function by IL-1β to aggravate RA, whereas inhibition has the opposite effect	[34, 85, 117]
	Block the osteoclastogenesis of MDSCs	MDSCs could directly differentiate into osteoclasts through NF-κB signaling	[84]
	Promote the expansion of MDSCs	Piperlonguminine (PL) could enhance the expansion of MDSCs to alleviate RA	[177]
	Apply MDSCs derived exosomes	G-MDSCs-derived exosomes attenuated CIA by decreasing the number of Th17 cells and Th1 cells in vivo and in vitro	[178]
	Enhance the positive effect of MDSCs on Treg cells	IL-10 derived from MDSCs could promote the proliferation of Treg cells and enhance the anti-inflammatory effect of Treg cells	[108]
Osteoarthritis	Strengthen the cross-talk among MDSCs, macrophages, and Treg cells	By analogy to RA, MDSCs may similarly alleviate OA through the cross-talk with macrophages, Treg cells	[34, 97, 108, 110–112, 114–116]
	Disrupt the potential promoting relationship between Th17 cells and MDSCs	Both Th17 cells and MDSCs were found to be elevated in the synovial fluid of OA patients like RA patients	[34, 105–107]
Orthopedic trauma	Appropriate administration of Arg-1 inhibitors or inhibition of Arg-1 expression by MDSCs	MDSCs express Arg-1 to restrain excessive inflammatory response for maintaining immune homeostasis and promote the proliferation of fibroblasts as well as the production of collagen to heal wound, but Arg-1 overexpression may also lead to post traumatic infections	[22, 123, 125, 182–184]
	Apply angiogenesis of MDSCs to periosteum	MDSCs express VEGFA, Ang2, and HIF-1α to promote the angiogenesis of the PMMA-induced membrane via STAT3 signaling	[127]
	Use drugs to induce MDSCs generation or adoptive transfer MDSCs	MDSCs could inhibit allograft rejection of various organ by interacting with other immune cells or secreting iNOS, IDO, Arg-1	[186, 187]