# Development of Anti-OSCAR Antibodies for the Treatment of Osteoarthritis
## 1 Introduction  
Osteoarthritis (OA) is the most common degenerative joint disease with accompanying inflammation and pain that can significantly impair patient quality of life. It is characterized by articular cartilage destruction, which is caused by dysregulation of the articular chondrocytes [1; 2]. These cells are exposed continuously to external mechanical forces and play key roles in cartilage homeostasis because they produce both the cartilage extracellular matrix (ECM) molecules and the metalloproteinases (MMPs) that degrade them [3; 4]. In OA, this anabolic/catabolic balance is tipped towards catabolism, cartilage degradation, chondrocyte apoptosis, and lacunar emptying [5; 6]. Additionally, as a whole-joint disease, OA elicits damage to other joint tissues, including subchondoral bone, meniscus, synovial membrane, ligaments, capsule, and infrapatellar fat pad [2; 7]. The non-cartilage tissues and cells around the joint also participate in OA pathogenesis. In particular, OA is associated with increased numbers of immune cells in the synovium that release pro-inflammatory cytokines such as interleukin (IL)-1\(\beta\), IL-6, and tumor necrosis factor (TNF)-\(\alpha\): These factors promote the cartilage catabolic functions of chondrocytes while simultaneouslydownregulating their cartilage anabolism [8]. Moreover, the pro-inflammatory factors also activate the osteoclasts and osteoblasts in the subchondral bone underneath the cartilage, which causes bone sclerosis that accelerates cartilage degradation [9; 10]. In addition to these cellular and biochemical factors, OA pathogenesis is also accompanied and affected by the biomechanical changes in chondrocytes and the articular cartilage [7; 11].  
Despite numerous studies on OA pathogenesis and extensive efforts to develop effective treatments for OA, there are currently no approved disease-modifying OA drugs (DMOADs) [12; 13], and OA treatment largely relies on pain relief agents or arthroplasty. In our recent study, we proposed that osteoclast-associated receptor (OSCAR) might be an effective DMOAD target [14]. OSCAR is a member of the leukocyte receptor complex (LRC)-encoded protein family characterized by the presence of extracellular immunoglobulin (Ig)-like domains [15; 16] and recognizes specific sequences in type I, II, and III collagens [17; 18; 19]. While OSCAR was first identified as a co-stimulatory receptor that is required for complete osteoclast differentiation [20], it is now clear that it is also expressed by other myeloid lineage cells, including monocytes, macrophages, neutrophils, and monocyte-derived dendritic cells. Moreover, it is associated closely with bone diseases [16; 21; 22]. Although articular chondrocytes usually do not express OSCAR or do so only at low levels, its expression is strongly upregulated in OA [14]. Our study also showed that when OSCAR was knocked out, mice that underwent OA-inducing destabilization of the medial meniscus (DMM) surgery demonstrated significantly less articular cartilage destruction. In vitro experiments then showed that OSCAR promotes OA by downregulating osteoprotegerin (OPG) and upregulating TNF-related apoptosis-inducing ligand (TRAIL), which in turn induces chondrocyte apoptosis. Notably, OA in mice was ameliorated by intra-articular injections of soluble human OSCAR-Fc fusion protein, which binds to murine as well as human collagen and acts as a decoy receptor [14]. Thus, OSCAR plays a vital role in OA progression and is a potential therapeutic target [22; 23].  
In the present study, we aimed to develop anti-OSCAR antibodies and demonstrate their capacity to block OSCAR activities, potentially slowing the progression of OA and ameliorating its symptoms. To achieve this goal, OSCAR-neutralizing antibodies were generated and optimized by phage display, and their efficacies were tested in vitro and in vivo. It is anticipated that the results from the study confirm the crucial role of OSCAR in OA pathogenesis, as well as provide a novel therapeutic approach to the treatment of OA.