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.
Highlights
Rheumatoid arthritis (RA) is an auto-immune disease marked by chronic and unrestrained inflammation, often in multiple synovial joints in the same patient
We have found that both AXL and MER play a suppressive role by alleviating joint inflammation and others have found that TYRO3 plays an enhancing role in bone degradation and synovial hyperplasia in experimental arthritis [5, 7, 10]
The ankle joint is the privileged site of disease in spontaneous arthritis models [14], but histological examination showed that the ankle joints in the TAM TKO mice appeared to be indistinguishable from their WT controls
Summary
Rheumatoid arthritis (RA) is an auto-immune disease marked by chronic and unrestrained inflammation, often in multiple synovial joints in the same patient. The synovium is infiltrated by both innate and adaptive immune cells which, together with the proliferation of the tissue-resident fibroblasts, leads to pannus tissue formation at the articular cartilage and bone interface. The TAM receptors–TYRO3, AXL and MER (gene name Mertk)–are a family of tyrosine kinases essential for immune homeostasis by negatively regulating the innate immune response. Together with their ligands Growth Arrest Specific 6 (GAS6) and Protein S (PROS1), they mediate the resolution of inflammation by facilitating efferocytosis [11]. We have found that both AXL and MER play a suppressive role by alleviating joint inflammation and others have found that TYRO3 plays an enhancing role in bone degradation and synovial hyperplasia in experimental arthritis [5, 7, 10] (manuscript under review)
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