Effects of synovial macrophages in osteoarthritis

Abstract

Osteoarthritis (OA) is a common degenerative disease in mammals. However, its pathogenesis remains unclear. Studies indicate that OA is not only an aging process that but also an inflammation-related disease. Synovitis is closely related to the progression of OA, and synovial macrophages are crucial participants in synovitis. Instead of being a homogeneous population, macrophages are polarized into M1 or M2 subtypes in OA synovial tissues. Polarization is highly associated with OA severity. However, the M1/M2 ratio cannot be the only factor in OA prognosis because intermediate stages of macrophages also exist. To better understand the mechanism of this heterogeneous disease, OA subtypes of synovial macrophages classified by gene expression were examined. Synovial macrophages do not act alone; they interact with surrounding cells such as synovial fibroblasts, osteoclasts, chondrocytes, lymphocytes and even adipose cells through a paracrine approach to exacerbate OA. Treatments targeting synovial macrophages and their polarization are effective in relieving pain and protecting cartilage during OA development. In this review, we describe how synovial macrophages and their different polarization states influence the progression of OA. We summarize the current knowledge of the interactions between macrophages and other joint cells and examine the current research on new medications targeting synovial macrophages.

Keywords: macrophages; osteoarthritis; polarization; review; synovial; treatment.

Figure 1

The comparison between normal joint and osteoarthritic joint Normal joint composed of joint cartilage, joint capsule, synovial membrane and articular cavity. Generally, synovial membrane has two layers. The inner layer, also called lining layer is mainly composed of synovial macrophage and synovial fibroblasts. The outer layer of synovial membrane also called sublining layer is connective tissue composed of blood vessels, collagens, interstitial macrophages, fibroblasts, adipocytes and a small number of lymphocytes. In osteoarthritic joint, the articular cartilage is damaged and the fragments of cartilage drift into articular cavity, forming loose bodies. The loss of cartilage leads to unevenly distributed loads on subchondral bones which can further cause osteoproliferation and sclerosis in the friction part as well as bone resorption and cystic degeneration in the periphery part. Moreover, both synovial membrane and articular capsule thicken in osteoarthritic joint due to inflammation. In hyperplastic synovial membrane, the most prominent changes are the hyperplasia of synovial and interstitial macrophages, the infiltration of T lymphocytes in sublining layer and the proliferation of blood vessels.

Figure 2

M1 and M2 polarization of synovial macrophages. M1 macrophages can be induced by Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and secret pro-inflammatory cytokines like interleukin (IL)-6, IL-1, R-spondin-2 (Rspo2), matrix metalloproteinase-13(MMP13), TNF-α. M2 macrophages can be induced by IL-4 and IL-10 and secret anti-inflammatory cytokines like IL-10, IL-1 receptor antagonist, suppressor of cytokine signaling 1 (SOCS1).

Figure 3

Interaction between synovial macrophages and other cells (A) Synovial macrophages and synovial fibroblasts: Synovial macrophages release interleukin (IL)-1, tumor necrosis factor-α (TNF-α) to increase the expression of IL-6, IL-8, matrix metalloproteinases (MMPs), nerve growth factor (NGF) in synovial fibroblasts. Fibroblasts stimulate macrophage proliferation by producing macrophage colony stimulating factor (M-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) (B) Synovial macrophages and osteoclast: Macrophages can transform into osteoclast when stimulated by IL-1, TNF-α, and especially receptor activator of nuclear factor κB ligand (RANKL). It is found synovial macrophages indirectly elevate RANKL level through CD4+ T cells and synovial fibroblast cells. Macrophages secret TNF-α and IL-1 to stimulate the differentiation of Th17 cells, which subsequently release IL-17 to induce the RANKL production of synovial fibroblasts. (C) Synovial macrophage and adipocytes: Fat tissues outside the joint secret adipokines like leptin, adiponectin and visfatin into blood circulation. Then adipokines get into synovial membrane and activate macrophage TLR to increase TNF-α, IL-1 expression. These macrophage-derived cytokines, in turn, lead to destruction and remodeling of local joint adipose tissue, which is a protective factor of osteoarthrosis. (D) Synovial macrophages and chondrocytes: Synovial macrophages release IL1, TNF-α to upregulate the expression of MMPs, A Disintegrin and Metalloproteinase with Thrombospondin-4 (ADAMTS-4) while downregulate Aggrecan and collagen II. In turn, injured cartilage produces soluble matrix degradation products (SMDP) and monocyte chemotactic protein-1 (MCP-1). It also leads to increased levels of two autocrine proteins S100A8 and S100A9 in macrophages. Both SMDP and S100A8/S100A9 function through activating Toll-like receptor (TLR) expressed on macrophages. MCP-1 functions by promoting macrophage aggregation. (E) Synovial macrophages and CD4+T cells: Synovial macrophages secret B cell Activating Factor (BAFF) to promote pro-inflammatory Th1 cells and Th17 cells while suppress anti-inflammatory Th2 response. Meanwhile, CD4+T cells also contribute to macrophage activation through CD40/CD40L co-stimulatory pathways.