Table 1.

Evidences from human and animal RA data: roles of MCs in RA pathogenesis

			Findings	Data source	Reference
Pathologic roles
	Roles on joint structure
		Synovitis	Correlation between clinical synovitis and MCs counts in RA synovium	Human	[6]
			More synovial MCs in active disease than burnt out disease	Human	[14]
			Treatment (intra-articular steroid injection) decreases MC population	Human	[15]
			c-kit/SCF positive MC hyperplasia correlates with local inflammation	Human	[18]
			Anti-apoptotic effect on synoviocyte via rho-mediated signaling	Human	[72]
		Erosion	Local accumulation of MCs is closely located with cartilage erosion	Human	[20,71]
			Tryptase from MC activates collagenase	Human	[41,70]
Secretory function				Human	[45]
		Chemoattractant	Chymase produces active form of chemerin	Human	[16,17,28,37]
		Histamine	Histamine secretion is elevated in RA synovium by MC stimulation/MC from active RA patients have greater capacity to secrete histamine	Human	[25,26]
		Lipid derivatives	Increased PGE2 and PGD2 secretion via MC stimulation	Human	[26,27,35,54,60]
		Proinflammatory cytokines	Secretion of TNF-α via MC stimulation	Human	[54]
			Secretion of IL-1β via MC stimulation	Human	[56]
			MC is the major source of IL-17A in RA synovium	Human	[27,28,35]
			IL-8, neutrophil chemotactic factor, is increased via MC activation	Human	[8]
Cell interactions with other immune cells
		B cell and autoantibody	B cell proliferation, activation, and ACPA production are upregulated by MC via cell to cell contact	Human	[8]
Experimental arthritis models
		Protease-deficient mice	Knock out of chymase or tryptase/heparin complex suppresses arthritis	Mice	[42,43,76]
		MC hyperactivity mice	CIA with MC hyperactivity induced by A20 deficient has higher arthritis incidence and arthritis severity score than control mice	Mice	[77]
		MC depletion via SCF/SCF receptor deficient mice	SCF deficient (KitlSl/KitlSl-d) and SCF receptor (c-kit) deficient mice (KitW/KitW-v) have resistance to arthritis induction in K/BxN serum transfer model and restore arthritis induction by intraarticular or intraperitoneal engraftment of MC	Mice	[78,79]
		Diphtheria toxin induced MC depletion mice	MC depletion mice via diphtheria toxin injection shows resistance to arthritis when arthritis is induced by collagen antigen (T cell dependent manner), especially in preclinical stage	Mice	[59,81]
Immunomodulatory roles
	Monocyte inactivation		Activated MC suppresses TNF-α production of CD14+ monocyte via IL-10 and histamine	Human	[28]
	Inverse correlation of serum/synovial tryptase with CRP		Serum tryptase level and synovial tryptase mRNA level, marker for MC activation, negatively correlate with serum CRP level of early RA patients	Human	[74,75]
Redundant roles
	MC depletion mice		KitW-sh/KitW-sh mice, MC depletion by c-kit mutation, is fully susceptible for arthritis via collagen antibody and collagen antigen induction	Mice	[82,83]
			K/BxN serum injection to Cpa3Cre/+ mice induce arthritis	Mice	[85]
	Diphtheria toxin induced MC depletion mice		MC depletion mice via diphtheria toxin injection has full susceptibility to arthritis in antibody-induced manner (T cell independent manner)	Mice	[81]
			MC depletion in established arthritis mice has no effect on clinical score	Mice	[59]

RA, rheumatoid arthritis; MC, mast cell; SCF, stem cell factor; PGE2, prostaglandin E2; PGD2, prostaglandin D2; TNF-α, tumor necrosis factor-α; IL, interleukin; ACPA, anti-citrullinated protein antibody; CIA, collagen-induced arthritis; CD, cluster of differentiation; CRP, C-reactive protein.