In view of the complexity of OA mechanism, a comprehensive plan for management of OA in different patients may include awareness in terms of educational plan, behavioral, psychosocial and physical interventions, as well as pharmacological treatment such as the use of topical, oral and intra-articular injection and also surgical treatment [19]. The principle of treatment should be addressed according to the degree of severity as well as the patient’s medical status to ensure that a personalized management strategy is tailored to their needs. The goals are to reduce symptoms and ultimately slow the disease progression, which may in turn improve quality of life and consequently reduce the health cost burden.

A multidisciplinary, patient-centered combination of education, self-management, exercise, weight loss with realistic goals, encouragement and regular reassessment is recommended for individuals with OA [20]. Commonly, topical NSAIDs, oral NSAIDs and tramadol are used to treat OA. However, inconclusive evidence has been shown for acetaminophen, non-tramadol opioids and intra articular injections of corticosteroids, hyaluronic acid (HA) and platelets rich plasma (PRP) [21]. Clinical trials of intra articular glucocorticoid injections have demonstrated a short-term efficacy in knee OA as well as for hand OA [19]. However, a recent report raised the possibility that specific steroid preparations or a certain frequency of steroid injections may contribute to cartilage loss; however, the clinical significance of this finding was uncertain, particularly since change in cartilage thickness was not associated with a worsening in pain, function or other radiographic features [22].

Surgical intervention is indicated in end stage OA when all previous treatment methods have failed, a significant loss in quality of life and when the patient is severely symptomatic. Surgery is an effective treatment option; however, the long-term success rate is not clear and may fail depending on the longevity of the implant. Surgical techniques may include osteotomy around the knee, unicondylar arthroplasty (partial knee replacement) or total knee arthroplasty based on the patients’ condition and degree of deformity or joint destruction [23].

Mesenchymal stem cells (MSCs) were first discovered in 1966 from the bone marrow [24] and hold the concept from postnatal progenitor [25]. They are also known as multipotent mesenchymal stromal cells which possess two major features, including the ability to differentiate into multiple lineages and the capacity of self-renewal. According to the International Society for Cellular Therapy (ISCT), MSCs must meet three minimal criteria [26]. Firstly, MSCs must exhibit plastic-adherence when grown in vitro. Secondly, MSCs must express the surface antigens CD73, CD90 and CD105 while lacking expression of CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR. Thirdly, MSCs must be able to differentiate into mesodermal cell types (i.e., adipocytes, chondrocytes and osteoblasts) when cultured under specific conditions.

Mesenchymal stem cells can be isolated from various tissues and are not restricted to mesodermal origin-type of cells such as bone marrow, adipose, muscle or bone. They were originally found in the bone marrow [24], but later studies identified MSCs in other tissues such as in the peripheral blood, brain, spleen, liver, kidney, lung, thymus, placental, umbilical cord and pancreas. Mesenchymal stem cells share a similar characteristic phenotype [26] despite their presence in different tissue sources, albeit with some additional features that represent their tissue origin [27]. Although MSCs can be isolated from almost every type of connective tissues [28], studies have shown that bone marrow represents the major source of MSCs ^[29][30][31][29,30,31].

Mesenchymal stem cells have become a popular cell source for therapeutic purposes due to their immunomodulation and regenerative properties ^{[32][33][34][35][36][37][38]}[32,33,34,35,36,37,38]. Mesenchymal stem cells possess the capacity to migrate to injured sites in response to other cells and environmental signals and also promote tissue regeneration orchestrated by the paracrine secretion of a broad repertoire of growth factors, chemokines and cytokines [39]. Through interaction with the host niche, MSCs were able to secrete bioactive mediators, such as growth factors, cytokines and EV that exert immunosuppressive, anti-apoptotic, anti-fibrotic, angiogenic and anti-inflammatory effects ^[40][41][40,41]. In addition, MSCs exhibited immunomodulatory functions by preventing immune cells’ activation or proliferation [42]. The immunomodulatory function of MSCs make them a good option for cell-based therapy, as the possibility for cell rejection is reduced.

The ability of MSCs to differentiate into various cell types enables their use as a tool in regenerative medicine. Mesenchymal stem cells have been reported to be successfully used as a therapy against many diseases and clinical conditions. At present, there are over 950 clinical trials worldwide that have used MSCs to treat various diseases [43], including bone and cartilage repair, diabetes, cardiovascular diseases, liver disease, immune-related, neurodegenerative diseases and spinal cord injuries. Mesenchymal stem cells have shown promising results in the clinical application of cell-based therapy. The efficacy of MSCs on bone regeneration in various orthopedic conditions has been widely demonstrated. Several clinical trials at different phases (I, II or III) have been performed for bone fracture repair using various sources of MSCs which were implanted either via direct injection or incorporated with osteogenic matrix or scaffolds which promoted bone repair and functions ^[44][45][46][44,45,46].

Regenerative medicine has become increasingly popular as a promising new approach for OA since articular cartilage has a limited capacity for spontaneous intrinsic repair, and may progress to OA, owing to the sparse distribution of highly differentiated chondrocytes, the low supply of progenitor cells and the lack of vascular supply [47]. This is evidenced by wide availability in clinical practice and by publications of many case series and clinical trials.

Cell-based therapy has been a promising option in OA because it is aimed at reversing the symptoms and pathophysiology of OA [48]. The ability of MSCs to differentiate between multiple lineages including musculoskeletal tissue supports the use of MSCs as an excellent source for degenerative musculoskeletal conditions such as in OA [49]. The therapeutic potential of MSCs in the treatment of OA is aimed at cartilage repair and restoration (Figure 2) [50].

The capability of MSCs to undergo chondrogenic differentiation assists in the regeneration of injured cartilage. In order to successfully enhance MSCs differentiation into chondrocytes, MSCs require soluble factors to promote differentiation such as transforming growth factor (TGF)-β, bone morphogenetic protein (BMP) and insulin growth factor (IGF)-1 ^[51][52][51,52]. The combination of BPM2/TGF-β in pre-chondrogenic medium resulted in high expression of chondrocytes specific genes such as collagen type II alpha 1 (COL2A1) and aggrecan (ACAN) [53]. Mesenchymal stem cells proliferation could also be enhanced by a low oxygen condition, which results in an increase of cartilage specific genes expression (COL2A1 and SOX9) and proteoglycan synthesis during chondrogenic differentiation [54]. Besides being able to regenerate or restore injured cartilage, MSC-based therapy also focuses on the inflammation attenuation. MSCs were shown to orchestrate immunomodulatory function of inflammatory responses through paracrine activities [55]. Adipose tissue-derived MSCs co-cultured with chondrocytes or synoviocytes showed a decrease in the expression of inflammatory factors such as IL-1β, TNF-α, IL-6 and CXCL8/IL-8 through the COX-2/PGE2 pathway as modulators, exerting anti-inflammatory effects in OA condition [56].

There were several strategies used by manipulating different MSCs sources and conditions for potential OA treatment [57]. Different sources of MSCs contribute to different outcomes in cartilage regeneration. For example, human skeletal stem cells (hSSCs) have shown the ability to generate into multilineage ossicles containing bone, cartilage and stroma, which have a potential for chondrogenic and osteogenic activities [58]. Apart from selecting different sources of MSCs, manipulating the MSCs in an in vitro culture condition also enhances chondrogenesis. A co-culture of human chondrocytes and chondro-progenitors (also known as cartilage cells) resulted in increased chondrogenic ability and increased cytokines and growth factors compared to bone-marrow derived MSCs [59]. Furthermore, controlling the culture condition also contributes to better chondrogenic differentiation such as culturing MSCs with TGF-β [60] or fibroblast growth factor (FGF)-2, 9 and 18 [61].

Direct intra articular injection of MSCs has been shown to improve the condition of OA patients [62]. Several studies have reported the use of intra articular injection of autologous bone-marrow-derived MSCs, which showed improvement in clinical symptoms and resulted in higher arthroscopic and histological grades than the control group ^[63][64][63,64]. In another study, an intra articular injection of autologous MSCs showed significant growth of cartilage and meniscus on magnetic resonance imaging (MRI), increased range of motion and modified visual analog scale (VAS) pain scores at 24-weeks post injection [65]. Intra articular injection of autologous bone marrow-derived MSCs showed significant improvement in terms of knee pain and quality of life during the 6-month follow-up [66].

Articular cartilage tissue engineering is another aspect that can be manipulated by using biomaterial constructs. Several biomaterials such as fibrin [67], biopolymer (chitosan) [68], synthetic polymers [69] and hydrogel [70] were widely used for their ability to degrade rapidly, their low immunogenicity and their ability to enhance MSCs proliferation and chondrogenic differentiation.

Another strategy to achieve chondrogenic differentiation of MSCs is via extracellular matrix (ECM) application by using synthetic or natural scaffolds. MSCs cultured in vitro in serum free conditions or in hydrogel or scaffold materials such as polymers, alginate beads and collagen sponges will eventually promote the differentiation of MSCs into chondrocytes [71]. Early pre-clinical studies have showed promising chondrogenic differentiation properties when MSCs were seeded on scaffolds ^[72][73][72,73]. Autologous transplantation of rabbit MSCs with HA gel sponges showed a well-repaired cartilage tissue which resembles the articular cartilage of the surrounding structure [73]. Another study has also used intra-articular injection of autologous adipose MSCs combined with HA which suppressed the OA progression and promoted cartilage regeneration [74]. The first autologous bone marrow-derived MSCs transplant embedded in vitro in a collagen gel was reported in 2004. A year later, the use of the matrix-induced autologous chondrocyte implantation (MACI) technique was reported by using a collagen bilayer seeded with chondrocytes [75]. Since then, many studies reported promising findings by using the MACI technique with various types of scaffolds, especially collagen due to its natural presence in the ECM [76]. Articular cartilage regeneration using allogeneic human umbilical cord blood-derived MSCs which were expanded in HA hydrogel demonstrated production of hyaline-like cartilage after one year and the regenerated cartilage persisted after three years [77].

The use of MSCs for articular cartilage regeneration has several limitations. A transcriptome analyses of human neonatal articular cartilage (hNAC) and MSC-derived cartilage has demonstrated that over 500 genes that are highly expressed in hNAC were not expressed in MSC chondrogenesis [78]. This suggests that in vitro MSC-derived cartilage may not represent the actual in vivo chondrocytes. In addition, in vitro cultured MSCs displayed a hypertrophic phenotype, thus limiting their application in articular cartilage tissue engineering [79]. Since MSCs are heterogenous, their numbers vary in tissues and different MSC sources may not be equivalent in terms of function ^[79][80][79,80].