Table 2.

Preclinical osteoarthritis models examining relationship between macrophages and pain.

OA model	Time point(s)	Results	Reference
Rat MIA	2 or 4 wk after MIA	Pain behaviors in 5-mg MIA rats were resistant to COX inhibitors and a steroid, but sensitive to anti-NGF and morphine; MIA induced macrophage infiltration in the synovium associated with high IL1b, NGF, NOS2, and COX2 expression in knee joint; clodronate depletion reduced macrophage numbers and pain behavior (grip strength and weight-bearing)	Sakurai et al., (2019). PAIN.
Mouse MIA	7 d after MIA	TrkA knock-in mouse joints had significant leukocyte infiltration and mast cells; Prostaglandin D2 synthase inhibitor prevented MIA-mechanical hypersensitivity in TrkA KI mice at doses ineffective in WT mice; microglial activation was observed 8 d after MIA	Sousa-Valente et al., (2018). Osteoarthritis Cartilage.
Rat MIA	3 wk after MIA	Increased ipsilateral expression of Cd11b+ microglia, but not astrocytes, in MIA rats	Lee et al., (2011). Mol Pain.
Mouse MIA	7 and 28 d after MIA	Increased ipsilateral microglial activation (Iba1+) by day 7 and significantly by day 28. GFAP expression in the dorsal horn was not changed.	Ogbonna et al., (2013). Eur J Pain.
Rat MIA	7, 14, 21, and 28 d after MIA	Microglia in the ipsilateral spinal cord were activated by day 7 and continued through day 28. Bilateral spinal GFAP (astrocytes) increases were seen at day 28, but not at earlier time points. Inhibition of glial activation by either nimesulide or minocycline attenuated pain behavior, activation of microglia in the ipsilateral spinal cord, and numbers of activated microglia and GFAP immunofluorescence.	Sagar et al., (2011). Mol Pain.
MIA	7 d after MIA	2-mg MIA, but not 1-mg MIA, induced microglial activation in both the ipsilateral dorsal and ventral horn by day 7	Thakur et al., (2012). PLoS One.
Rat MIA	7 d after MIA	Increased microglia in the ipsilateral and contralateral dorsal horn by day 7; specific ablation of spinal microglia through intrathecal injections of the immunotoxin, saporin, conjugated to the Mac1 antibody (Mac1-saporin), attenuated mechanical allodynia by days 5 and 7 after MIA	Mousseau 2018 Science Advances
Mouse DMM	4, 8, and 16 wk after DMM	CCR2 null mice develop mechanical allodynia at 4 wk, but resolved by 16 wk; CCR2 null mice lacked movement-provoked pain at 8 wks; macrophages infiltrate DRG at 8 wk maintained up to 16 wk after DMM; CCR2 null mice have no macrophage infiltration in DRG	Miller et al., (2012). PNAS.
Mouse DMM	4, 8, and 16 wk after DMM	Increased activated CX3CR1+ and Iba1+ microglia at 8 and 16 wk in WT mice, but not 4 wk; DRG cultures have increased CX3CL1 levels at 8 and 16 wk; Adamts5 null mice do not develop mechanical allodynia up to 16 wk after DMM and do not have increased CX3CL1 levels.	Tran et al., (2017). Osteoarthritis Cartilage.
Mouse DMM	16 wk after DMM	S100A8 and a2-macroglobulin treatment in DRG cultures stimulated MCP-1 release; TLR4 inhibition reversed this effect; TLR4 null mice were not protected from mechanical allodynia or joint damage in DMM	Miller et al., (2015). Arthritis Rheumatol.
Mouse CiOA	Day 20–42 after CiOA	Irf4, CCl17, and CCR4, but not TNF knock-out mice showed decreased cartilage destruction, osteophyte size, and weight-bearing pain behavior; CCL17 and Jmjd3 neutralization attenuated both joint destruction and pain; Ccl17 mRNA expression was only found in macrophages and was controlled by GMCSF and IRF4 signaling	Lee et al., (2018). Arthritis Res Ther.
Rat CiOA	6 wk after CiOA	GFAP expression on satellite glial cells in the DRG and on astrocytes in the dorsal horn was significantly increased after CIOA; Iba1+ microglia were also upregulated in the dorsal horn after CIOA; inhibition of glial activation by fluorocitrate improved pain behaviors (knee-bend test and gait deficits) in CIOA mice	Adaes et al., (2017). Molecular Pain.

CiOA, collagenase-induced OA; DMM, destabilization of the medial meniscus; GFAP, glial fibrillary acidic protein; MIA, monoiodoacetate-induced; OA, osteoarthritis, WT, wild type.