3. Stem Cells
Stem cells are precursor cells. The cells have the ability to self-renew, can stay in an undifferentiated state, show high plasticity, can transdifferentiate, and have quite a long life span. There are two pathways through which these cells can divide: (1) symmetric division—the daughter cell is identical to the antecessor and both cells remain as undifferentiated stem cells, or (2) asymmetric division—the daughter cell has limited developmental potential, which is the way stem cells differentiate and specialize into lineages
[23][28]. These cells are unspecialized but can give rise to other specialized cell types
[24][29]. There are two possible origins of stem cells. They may either be embryonic (ESCs), coming from a very early embryo or blastocyst, or they may be postnatal/adult stem cells (ASCs), which are undifferentiated, capable of self-renewal, and responsible for adult tissue regeneration
[23][24][28,29].
There are various types of adult stem cells. There are hemopoietic stem cells (HSCs) that give rise to all blood cell components, including neutrophils, lymphocytes, natural killer cells, dendritic cells, macrophages, and monocytes. These HSCs are of mesodermal origin, are derived from bone marrow, and generate all blood cell types
[23][28]. There are also mesenchymal stem cells (MSCs) that give rise to osteoblasts, chondrocytes, adipocytes, and the reticular stroma.
4. Mesenchymal Stem Cells (MSCs)
The most useful stem cell for tissue engineering and implantation for the treatment of OA are mesenchymal stem cells (MSCs). These are usually restricted to forming only mesodermal specific cell types (adipocytes, osteoblasts, myocytes, and chondrocytes), but several are able to differentiate into other cell varieties. The trophic effects of MSCs include the secretion of bioactive molecules that are anti-apoptotic, immunomodulatory, angiogenic, ant-scarring, and/or chemoattractant
[25][26][32,33]. Stem cells in adults reside in niches, which are limited and have a specialized microenvironment. These cells have a physical anchoring site with a set of factors that control the cell number, activation, proliferation, self-renewal, or lineage differentiation. The microenvironment of the niche, with all its factors and signaling modulators, maintain homeostatic regulation of the stem cells by the up- or downregulation of the signaling pathways.
The paracrine effects of MSCs can be divided into three types: trophic, immunomodulatory, or chemoattractant. The trophic effects mainly stimulate neighboring parenchymal cells. These include the inhibition of apoptosis, and the support of regeneration, stimulation, maintenance, proliferation, and differentiation of tissue specific progenitors
[25][32]. The immunomodulatory aspects may include an immunosuppressive effect, and immunoactivity mediation by direct cell–cell contact and by the secretion of bioactive molecules. The cells involved in interactions may include dendritic cells, B cells, T cells—including T regulatory cells and T helper cells—and killer cells.
Although MSCs can be found in various niches, they have many functional similarities. MSCs derived from various sources display different toll-like receptors (TLRs), which have functional properties, and respond to stimulation by TLRs agonists. TLRs are transmembrane proteins which play critical roles in the immune system by mediating inflammatory responses, primarily through the binding of ligands. MSCs are not spontaneously immunosuppressive, and the presence of inflammatory mediators may be essential for MSC-mediated immunosuppression and modulation of the functional properties.
5. Causes of Osteoarthritis
Unfortunately, chondrocytes may over-produce matrix-degenerating enzymes, such as matrix metalloproteinase 13 (MMP-13)
[2][27][2,36]. While MMP-13 is needed for the healthy maintenance of articular cartilage, its overproduction can promote OA. In the osteoarthritic joint, there is a great mobilization of macrophages, and this consequently produces cytokines. The two major pro-inflammatory cytokines that have an impact on the progression of cartilage breakdown are IL-1β and TNF-α, which work by promoting catabolic and degradative processes. Experiments conducted on mice have suggested that a decrease in the TGF-β level (produced by synovial macrophages) induced osteophyte formation
[16][27][17,36].
There are catabolic and pro-inflammatory mediators in OA, such as cytokines and nitric oxide, which play an important role in triggering the pathophysiology of OA by instigating the formation of free radicals (reactive oxygen species). The overproduction of cytokines triggers inflammatory stress that is responsible for degenerative and inflammatory tissue damage. Another type of mechanism is a destructive process activated by reactive oxygen species, which involves the induction of chondrocyte apoptosis
[9].
6. Traditional Therapy and Models of OA
There is no effective therapy against the progression of OA. Currently, pain management, activity modification, and weight loss are prescribed in the early stages, but in the advanced stages there are very few options available. There are a few alternatives to help with moderate OA such as high tibial osteotomy of the knee joint, for example, in order to attempt to realign that particular joint. However, the patient must not be in too advanced of a stage of the disease
[28][39]. Another traditional therapy has been hyaluronic acid; however, artificial hyaluronic acid can only provide temporary pain relief
[29][40]. Joint replacement is generally the therapeutic procedure employed
[30][41]. Animal models of OA of the knee have included horse, sheep, rat, mouse, rabbit, and guinea pig
[30][41], as well as a caprine model (goats)
[31][26] and dogs
[32][33][42,43]. The large-animal models have had the most advantage in modelling the human progression of the disease, as compared to small-animal models, since they have a larger body, longer life, long-term follow-up, and are a better simulation of human pathology
[34][44].
The main aim of traditional pharmacotherapy for OA is pain relief or reduction. Commonly used pharmacotherapies are acetaminophen, non-steroidal anti-inflammatory drugs, and opioid analgesics (tramadol). Intra-articular injections of corticosteroids are also applied; however, these treatments do not inhibit the decay process and adverse events are frequently noticed with prolonged use of these pharmacotherapies
[2]. The prolonged administration of drugs is an inherent problem in most chronic diseases and is associated with possible gastrointestinal, renal, and hepatic adverse events
[17][18]. The traditional multi-modal therapy of inflammation and pain reduction includes long-term cyclo-oxygenase-inhibiting non-steroidal anti-inflammatory drug (NSAID) therapy, physical therapy, diet, weight management, and dietary supplements.
7. Regenerative Medicine
The most important and most difficult task of cartilage tissue engineering is creating a functional substitute for native cartilage
[5][35][5,34]. In 1993, Langer and Vacanti defined tissue engineering as accentuating the interdisciplinary character to restore, maintain, or improve tissue function
[3]. Regenerative therapy/cell therapy, especially with the use of stem cell technology, may one day fulfil the requirements of delaying OA progression and joint tissue repair
[2][35][2,34]. In 1968 in the United States, the first successful allogenic stem cell graft in humans using donor bone marrow was undertaken
[36][31]. This was perhaps the first step in using mesenchymal stem cell technology.
Chondrocyte implantations for cartilage regeneration has quite a long history, dating back to 1994
[37][46]. The clinical use in human patients actually began in 1987
[4]; however, since OA has such complex degenerative joint changes in different age groups of patients, the therapy was not fully effective. Mesenchymal stem cells are preferred since they may be collected from different tissues, are actively immunosuppressive, have a capacity for chondro-differentiation, and have a high proliferation potential
[2][13][2,14]. Bone marrow and adipose derived MSCs have been most commonly used for OA treatment and repair. The disadvantage of autologous chondrocytes as regenerative cells is that they have a limited capacity to proliferate
[17][38][18,47].
8. Mesenchymal Stem Cells and the Treatment of OA
As previously mentioned, but worth reiterating, there are two types of cells used for cartilage engineering: (1) chondrocytes, which were the first to be used and are obtained by the isolation and amplification of autologous chondrocytes unless the monolayer cultured chondrocytes rapidly lose their phenotype, and (2) mesenchymal stem cells (adult MSCs from different sources). Adult MSCs are of major interest in tissue engineering. MSCs that have already been applied have been sourced from bone marrow (most popular source), adipose tissue, muscles, periosteum, perichondrium, synovium
[3][26][3,33], umbilical cord blood, as well as muscle and peripheral blood
[1][39][1,48].
MSCs seem to provide some important advantages over chondrocytes when considering the treatment of degenerative joint diseases. They are easier to culture, more rapidly proliferate, and can specialize to become all tissues within the joint. Moreover, the paracrine activity seems to be most beneficial in treating OA conditions. The anti-inflammatory and immunomodulatory properties of MSCs play a pivotal role in orchestrating the reparative response of damaged joint tissues
[27][30][40][36,41,49]. Mesenchymal stem cells (MSCs) interact with immune cells and are responsible for the modulation of a number of effector functions, immunomodulatory properties, migratory abilities, the induction of peripheral tolerance, inhibiting the release of pro-inflammatory cytokines, and the promotion of tissue repair.
The advantage of using MSCs for treating OA include their capacity to differentiate into chondrocytes and their potential to prevent chondrocyte apoptosis and to prevent the overall process of degeneration (through a paracrine effect)
[41][37]. They also modulate the activity of the immune system (via an immunosuppressive function), secrete cytokines and chemokines, suppress T cell proliferation, and inhibit the respiratory burst in neutrophils. The environment is responsible for modulating the balance between the pro-inflammatory and anti-inflammatory properties of MSCs
[40][49]. Many pre-clinical and clinical trials have employed MSCs for OA management. The most important issues are the accuracy of evaluating the processes of disease progression, and the evaluation of cartilage regeneration. For quite some time, MSCs were regarded to be ‘immune privileged’, meaning that they are hypoimmunogenic. However, recent studies have suggested that MSCs may not be ‘immune privileged’, but “immune evasive”.
The reason for allogenic MSC transplantation, rather than an autograft, is that there is a suspicion that OA patients, especially in advanced stages, are not the best donors of MSCs for their own treatment. Some authors have suggested that OA patients may have systemic depletion and derangement of MSCs. Cell differentiation and proliferation capacity may be too low to make a positive difference in the rebuilding of joint homeostasis. This negative impact on MSC dysfunction seems to be greater in bone marrow-derived cells than in MSCs derived from adipose tissue
[30][41].