1. INTRODUCTION
Osteoarthritis (OA) is one of the most common debilitating diseases encountered globally. The clinical symptoms of OA are pain and functional impairment that includes joint stiffness and dysfunction. It affects 30 million people in the U.S.(Lawrence et al., 2008). In 80% of patients with OA have some degree of movement impairment. This leads to diminished performance in the workplace, and 25% of patients cannot perform the main activities of their daily life, which often leads to social isolation and depression(Kean, Kean, & Buchanan, 2004). Nevertheless, in spite of decades of drug research and development, no disease-modifying drug for osteoarthritis has been approved for use in humans(Gerwin, Hops, & Lucke, 2006). Such a drug could slow progression by reducing the rate of cartilage degeneration. The current standard of care focuses on pain relief only after symptoms are present, by the use of acetaminophen, NSAIDs COX2 inhibitors and corticosteroids.
One of the hallmarks of OA is the pathological structural changes that occur in the subchondral cortical, trabecular bone and subarticular structures. The early stage in the course of the disease is a significant increase in bone turnover and re-modelling (both bone formation and resorption) of the bone cartilage interface, especially in areas underlying damaged cartilage. The trabecular bone, and the cortical subchondral plate thickens and becomes increasingly irregular (Buckland-Wright, 2004). The biomechanical factors, such as localized increased load on the subarticular bone beneath areas of damaged cartilage, and pathobiochemical influences, such as enhanced release of cytokines and tissue growth factors (Haringman, Ludikhuize, & Tak, 2004; Sweeney & Firestein, 2004). Key contributors to catabolic processes include, interleukin-1β (IL-1β) and matrix metalloproteinases (MMPs), growth factors and free radicals, among others(Steinberg & Zeggini, 2016). Bone morphogenetic proteins (BMPs) and insulin growth factor 1 (IGF1) are endogenous anabolic factors that stimulate cartilage generation and remodelling(Fan et al., 2004; Lajeunesse, 2004; Matsumoto, Gargosky, Iwasaki, & Rosenfeld, 1996; Sandell & Aigner, 2001). In addition, health problems of excessive osteoclast formation and bone resorption can cause an imbalance in bone remodeling and thus induce many adult skeletal diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, multiple myeloma and metastatic cancers, premature menopause and low levels of testosterone and estrogen in men, all potentially leading to changes in cartilage homeostasis.
Andrographolide (AG) is the major active principle isolated from the plant Andrographis paniculate and having a similar size or containing an estrogen-like molecule(Cauley et al., 2008). It is a well-known traditional medicinal plant in India, Thailand, and China. This plant is widely recognized for its therapeutic and biologically active properties. Many studies have focused on andrographolide (C20H30O5) activity, for examples, anticancer(Khan, Khan, Farooqui, & Ansari, 2018; Liao et al., 2019), anti-viral(Paemanee, Hitakarun, Wintachai, Roytrakul, & Smith, 2019; Wintachai et al., 2015), anti-thrombotic(Lu et al., 2012; Mussbacher et al., 2019), hepatoprotective(Chua, 2014; Singha, Roy, & Dey, 2007), and anti-inflammatory properties(Tan, Liao, Zhou, & Wong, 2017). Furthermore, AG has been reported to have inhibitory effects on osteoclastogenesis and osteoclast function in vitro and in vivo (Zhai et al., 2014). Due to the lack of cytotoxicity and evidence of the effects of AG on multilineage differentiation in human mesenchymal stem cells, this study’s aimed is to investigate the effects of AG on the in-vitro cytotoxicity, and human mesenchymal stem cell differentiation in order to identify potential mechanisms of action.
Stimulating bone and cartilage formation with biologically active pharmaceuticals derived from natural sources is a direction worth investigating for the treatment of homeostasis of bone diseases and/or bone remodeling in regenerative medicine field.