Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.

Osteoarthritis (OA) of the knee is a chronic, indolent disease that affects all genders, ages and races but is known to be most common in the elderly and in obese people. A degenerative disease of the connective tissue, it mainly affects the articular cartilage (Figure 1)[1]. The definition of knee OA varies in reported studies and includes self-reported knee OA (obtained from a questionnaire), radiographic definitions of knee osteoarthritis, and symptomatic knee OA (self-reported joint pain and radiographic evidence of OA)[2]. Symptoms may include joint pain, stiffness and tenderness. Furthermore, as the cartilage substance decreases, the bone surface may also become affected. This results in development of osteophytes (bone spurs) and direct bone-bone contact. In addition to the stiffness of the joint, the patient tries to avoid pain by minimizing joint movement, which leads to muscle atrophy and laxity of the ligaments[1-4].

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Figure 1 Pathophysiology of knee osteoarthritis. Comparison between a normal and diseased joint (Illustration created after Felson[3] and Buja et al[⁴])

The pathogenesis of knee OA have been linked to biomechanical and biochemical changes in the cartilage of the knee joint (e.g., inability to withstand normal mechanical stresses, limited supply of nutrients and oxygen, inadequate synthesis of extracellular matrix components, increased synthesis of tissue-destructive proteinases (matrix metalloproteinases and aggrecanases) and overall apoptosis of chondrocytes)[4-7]. Recently, synovial inflammation has also been accredited as a factor limiting knee cartilage repair. Moreover, it correlates to clinical signs of knee OA such as swelling of the knee and inflammatory pain[7,8]. It is believed that synovial inflammation is a response of synovial macrophages to cartilage debris and catabolic mediators entering the synovial cavity[8,9].

In regards to the epidemiology of knee OA (Table 1), studies indicate that knee osteoarthritis in men aged 60 to 64 is usually found in the right knee (23%) than in the left knee (16.3%), while distribution seems to be more evenly balanced in women of the same age (right knee, 24.2%; left knee, 24.7%)[6,10]. A variety of endogenous (e.g., age, sex) and exogenous (obesity, patient’s lifestyle) risk factors for OA have also been outlined[2,6,11-14]. Recently, a number of genome wide association studies (GWAS) (e.g., Rotterdam GWAS[15], Tokyo GWAS[15], Chingford Study[16]) have highlighted the significance of gene mutations (e.g., in GDF5) for the development of knee OA[15-21]. Additionally, ross-sectional studies indicate that the risk of knee OA is 1.9 to 13.0 times higher among underground coal miners when compared to a control population; presumably, due to frequent work in the kneeling or squatting position[6]. Construction workers, especially floorers, also have a significantly elevated prevalence of knee OA[6].

As of clinical diagnosis of knee OA, it is complex as during the physical examination of the patient it is needed to confirm and characterise joint involvement, as well as to exclude pain and functional syndromes linked to other causes (e.g., inflammatory arthritis or damaged meniscus)[3,11,22]. In addition to non-surgical treatments for this condition such as physiotherapy, diet rich in vitamin D and supportive sport (e.g., swimming)[10,23,24], there are several medicinal and homeopathic products on the market, which promise pain relief and a decrease in symptoms. However, researchers are keen to investigate new treatments to combat OA of the knee.

Self-regeneration of the cartilage, which includes chondrocytes, ground substance (cartilage matrix) and elastin fibers, is a slow process which results in new cartilage substance that is not stable for intensive burdens. The fluid inside the joint contains mesenchymal stem cells (MSCs) which can differentiate into chondrocytes, but new deposited cartilage is very fragile and can be destroyed by applying a minimal amount of stress on the joint. Additionally there is only a limited quantity of MSCs in the joint available to differentiate and the process of differentiation is slow[1,25].

The aim in using stem cells is to support the self-healing process of the knee joint cartilage which results in relief from OA symptoms[26-32]. This treatment should be used in conjunction with additional treatment in order to improve patients’ functional status and quality of life. However, osteoarthritis cannot be cured by any radical treatment at the moment.

The stem cell candidates for use in these therapies are multipotent adult MSCs, because they are available in several tissues, including in the fluid inside the joint, and have the ability to differentiate into cells of the chondrogenic lineage[33,34]. Pittenger et al[35] have described that MSCs could be cultured without losing their multilineage differentiation potential and it has been shown that MSCs are capable of undergoing chondrogenic differentiation both in-vitro and in-vivo. MSCs can be harvested from bone marrow, periosteum, trabecular bone, adipose tissue, synovium, skeletal muscle and deciduous teeth[36]. Regardless of their origin they have the capacity to differentiate into many cell types, including cells of connective tissue lineages, including bone, fat, cartilage and muscle[26,37]. MSCs were first identified in the pioneering studies of Friedenstein and Petrakova (1966)[33] and are of major interest of research in the treatment of arthritis, in particular OA.

Multipotent adult mesenchymal stem cells are extensively investigated - in particular their behaviour in cell culture: how do they stay multipotent after several passages; how is chondrogenesis triggered in MSCs[32]. There are no definitive markers identified for MSCs yet, but the immunophenotype is positive for the proteins and enzymes STRO-1, CD73, CD146, CD105, CD106, CD166 and negative for CD11b, CD45, CD34, CD31 and CD117. These are the most reliable for characterizing MSCs[34,36].

There are several other criteria which must be considered when growing MSCs in culture. One of the most crucial criteria is the availability of characterized factors which stimulate the anabolic activity in cartilage including transforming growth factor (TGF)-β, bone morphogenetic protein (BMP), fibroblast growth factors (FGF), insulin growth factor (IGF)-1, hedgehog (hh) and Wingless (Wnt) proteins[26]. These factors are signalling proteins that belong to the tyrosine kinase family of proteins (transmembrane proteins) that activate several downstream processes leading to cell proliferation, survival, growth and a reduction in apoptotic signalling.

Growth factors like FGF2 or transforming growth factor beta induce a positive differentiation of MSCs[38]. Moreover, the development of methods was required to develop the cartilage phenotype without hypertrophy, fibrinogenesis or ossification. In addition, a delivery system was devised to target cells in a lesion, but without inhibiting their chondrogenic differentiation or the integrity of repaired tissue[39].

In recent years several clinical protocols for MSCs have been tested[26-32,40]. In general, MSC related therapeutic approaches have a significant advantage to traditional surgical approaches such as autologous chondrocyte transplantation: no cartilage biopsy is necessary, thus no external stress and cellular damage are applied at the donor-site articular surface[31]. Moreover, direct intra-articular injection of MSC is perceived as a technically simple way to treat advanced OA of the knee[32].

In recent years the role of stem cells in health and disease is a topic of high interest for biomedical research, especially regenerative medicine[33,45,46], including non-pharmacologic treatment of knee OA[25,40,47], and drug discovery[48-50]. At the moment there is an increase in the number of clinical cases utilizing stem cell therapy for knee OA, however, many clinical protocols are still under development[26,30,40].