Tyro3/Axl/Mertk-deficient mice develop bone marrow edema which is an early pathological marker in rheumatoid arthritis

Abstract

Rheumatoid arthritis is an auto-immune disease of the synovial joints, hallmarked by chronic inflammation and subsequent progressive tissue destruction. TYRO3, AXL and MER (gene name Mertk) (TAM) receptors are part of a negative feedback signaling system in the immune reaction and mediate efferocytosis thereby tempering the inflammatory process. We have shown that Axl-/- and Mertk-/- mice develop more severe arthritis whereas activating these receptors by overexpressing their ligands Pros1 and Gas6 ameliorates arthritis. Mice genetically ablated for the three genes of the TAM receptor family Tyro3/Axl/Mertk (TAM triple knock-out or TKO) have been described to spontaneously develop macroscopic signs of arthritis. In this study we aimed to analyze arthritis development in TAM TKO mice histologically to determine the extent and sequence of pathological changes in the joint. Ankle joints of three different age groups, adolescence (14 weeks), mature adult (34 weeks) and middle-age (52 weeks), of TAM TKO or wild-type mice were examined macroscopically, histologically and immunohistochemically. Surprisingly, until the age of 52 weeks, none of the mice examined developed spontaneous macroscopic signs of arthritis. There was no synovial inflammation nor any signs of damage to the cartilage or bone. However, bone marrow edema was observed in TAM TKO mice in the two latter age groups. The infiltrate in the bone marrow was characterized by both myeloid cells and lymphocytes. This study showed that TAM TKO mice developed a pre-stage (pre-clinical phase) of arthritis marked by bone marrow edema.

Genomewide Association Study of Acute Anterior Uveitis Identifies New Susceptibility Loci

“…Axl/Mertk double knockout mice are susceptible to T-cell mediated uveitis, 44 and Tyro3/Axl/Mertk triple knockout mice develop bone marrow edema and macrophage and B-cell and T-cell infiltration, consistent with changes seen in spondyloarthritidies. 45 MERTK is expressed at high levels in the ovaries, prostate, testis, lungs, retinas, and kidneys, and at lower levels in the heart, brain, and skeletal muscle. 46 MERTK is also expressed in macrophages, dendritic cells, natural killer (NK) cells, NKT cells, and platelets.…”

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis

“…In addition, activation of TAM receptors induces, among others, suppressor of cytokine signaling (SOCS) proteins 1 and 3, which reduce production of numerous cytokines [ 9 , 14 , 15 ]. Although we recently showed that Mer and Axl play a protective role in mouse models of RA, the exact function of TAM receptors in RA patients remains largely unknown [ 16 – 18 ]. TAM receptors can be cleaved from the cell surface, leading to shedding of their soluble ectodomain and consequently a soluble form of the receptor [ 19 , 20 ].…”

New Insights into the Role of Tyro3, Axl, and Mer Receptors in Rheumatoid Arthritis

“…Following the initial report of the triple TAM KO phenotype, a recent work on the same mice quite surprisingly showed that, in comparison with wild types (WT), KO littermates had neither macroscopic nor histological evidence of inflammatory arthritis in ankle joints until the age of 52 weeks [72]. As suggested by the authors, a different phenotype observed in a genotypically identical animal model may be justified by changes in the interplay between genetic and environmental factors, including, for example, improved cleanliness of facilities and modifications of the microbiota.…”

“…The latter, in particular, could represent an exciting link with RA as the dysbiosis seems to be a promoter of inflammatory arthritis [73]. Despite not showing clinically evident arthritis, however, both adolescent and adult TAM -/mice had significantly more marked bone marrow oedema, which is an early sign of arthritis [72].…”