**1. Introduction**

Arthritis appears in over 100 identified diseases that can damage any joint in the body, causing inflammation that results in pain, stiffness, swelling, and decreased motion [1,2]. As the leading cause of disability among adults [3], arthritis has been diagnosed in approximately 54.4 million people in the U.S. alone [2,3]. Since arthritis affects people of all ages, sex, and races, its prevalence is expected to increase sharply shortly and turns to be a tremendous economic burden on patients and society [3–5]. Especially, osteoarthritis (OA) is the most common form of arthritis and affects around 18% of women and 10% of men over 60 [4,6]. Alarmingly, recent studies suggest that younger adults are also suffering from OA [7] associated with trauma and occupation-related joint stress [8]. Unfortunately, there are currently no approved disease-modifying osteoarthritis drugs (DMOADs) that can prevent, stop, or even restrain the progression of OA [4,9,10]. Thus, the Osteoarthritis Research Society International (OARSI) recognizes OA as an incurable condition [4]. When considering productivity loss due to OA, estimates are between 0.25% and 0.50% of the gross domestic product (GDP) [11]. Therefore, the biomedical burden of OA is enormous, growing, and inadequately addressed.

Since OA is primarily characterized by disordered articular cartilage homeostasis with subsequent inflammation and degradation, the major effects of developing an ideal OA-combating agent were focused on protecting and reestablishing the hyaline cartilage [12]. However, due to the development of the imaging and diagnosis techniques, synovitis has also been recognized as common in OA in the past decade and offers another potential target for treatment [13]. In response to this finding, glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed OA medications [14]. For instance, glucocorticoids, such as prednisone and cortisone, are broadly used for current arthritis treatment due to their anti-inflammatory potency [15–17] and achieving short-term improvement in symptoms of OA [18,19]. However, the effect may vary substantially in different patient groups [18,20]. More importantly, multiple adverse side-effects in the musculoskeletal, cardiovascular, and gastrointestinal systems [20–22] challenge the application of glucocorticoids as a safe treatment option. Meanwhile, NSAIDs do not adequately control OA progression [23], while their long-term usage is associated with potentially harmful adverse effects [24]. Even more disappointing, the efficacy of disease-modifying antirheumatic drugs (DMARDs) that postpone rheumatoid arthritis (RA) progression by slowing or suppressing inflammation has not been replicated in OA clinical trials via systemic or local administration [25–27], which may be attributed to their failure on directly managing cartilage destruction—the primary cause of OA [4,28].

Although hyaline cartilage and synovium can cross-talk via synovial fluid [14] and share some inflammatory signaling pathways [29], it is worth noting that they are two distinct types of tissues and may respond differently to the same stimulation, such as OA. Strategically, the agents benefiting one tissue with the expense of another should be avoided for OA treatment. On the other hand, the biomarker(s) has/have similar OA-responsive expressions in cartilage and synovium should be a more suitable marker for OA progression than those only altered in one of these two types of tissues. Moreover, the bioactive molecule that defends and rebuilds both hyaline cartilage and synovium is favorable for OA control and treatment with no doubt. Therefore, publicly available transcriptome datasets of knee articular cartilage and synovial tissue were integrated and analyzed in the current study to gain insight into developing the new generation of DMOADs that promote both cartilage and synovium.
