Current Concepts: The Role of Mesenchymal Stem Cells in the Management of Knee Osteoarthritis

Osteoarthritis (OA) is a disease process resulting from the failure of chondrocytes to repair damaged articular cartilage in synovial joints.2 Increased synthesis of tissue-destructive proteinases such as matrix metalloproteinases, increased chondrocyte apoptosis, and insufficient extracellular matrix generation result in a cartilage matrix that is unable to withstand normal mechanical stresses.5 This leads to progressive cartilage loss, subchondral bone remodeling, osteophyte formation, and synovial inflammation.20,34 These degenerative changes can ultimately result in significant disability and chronic pain. The number of adults in the United States with osteoarthritis is expected to nearly double from 21.4 million in 2005 to 41.1 million by 2030.31 Direct and indirect medical costs relating to arthritis and associated comorbidities are estimated to exponentially increase in the coming decades.6 In 1997, the total medical expenditures for arthritis and other rheumatic conditions were $233.5 billion. These costs increased to $321.8 billion by 2003 and have continued to rise on an annual basis.31 The prevalent strategy for managing OA is to exhaust conservative measures in an effort to delay major reconstructive joint surgery, particularly in younger adults. The goals of treatment are to decrease joint pain and improve function resulting in improved quality of life metrics for patients. Low-impact, aerobic exercise significantly reduces pain and improves function in patients with early OA.64 More specifically, strengthening exercises seem to be superior in reducing pain and impairment, and aerobic exercise leads to improved long-term functional outcomes.64 In patients with medial unicompartmental OA, valgus unloader braces reduce external varus moments and medial compartment load and improve pain and function when compared with simple neoprene sleeves.8 However, there is limited high-level evidence to suggest that valgus- or varus-directing knee braces for medial or lateral unicompartmental knee OA, respectively, are more effective than a placebo.8,25 Pharmacological pain control remains the mainstay of treatment for symptomatic knee OA. Nonsteroidal anti-inflammatory drugs have a statistically significant pain-reducing effect when compared with placebo and acetaminophen, although this effect is not clinically significant.64 Other options include nonselective oral nonsteroidal anti-inflammatory drugs plus a gastroprotective agent or cyclooxygenase-2 inhibitors. For patients with marked pain who are not good candidates for surgery, opioid analgesics may be considered in spite of physician and patient concerns regarding side effects and improper use.29 Intra-articular corticosteroid treatment, although popular, only relieves pain in the short term, with its greatest effect after 1 week and diminishing thereafter.29 In addition, intra-articular corticosteroid injections combined with lidocaine can be cytotoxic for chondrocytes. Its frequency and patient selection must be carefully considered.7,48 Intra-articular viscosupplementation has become increasingly common for the treatment of symptomatic knee OA. However, its efficacy remains controversial. In several clinical studies, exogenous hyaluronic acid (HA) reduced the production and activity of pro-inflammatory mediators and matrix metalloproteinases, while enhancing native chondrocyte HA and proteoglycan synthesis, and even altering the behavior of immune cells.15 HA is also important for modulating tissue hydration and osmotic balance.15 A meta-analysis published in the Journal of the American Medical Association in 2003 suggests that intra-articular HA knee injections for OA may not result in a clinically significant difference when compared with placebo.32 However, a Cochrane review3 concluded that viscosupplementation, when used in specific clinical settings, is an effective treatment for knee OA and may provide longer term benefits when compared with intra-articular corticosteroids.22 The results of HA therapy may be related to variations in the molecular weights of HA products as well as varying degrees of heterogeneity of HA (viscosity and elasticity). Platelet-rich plasma (PRP) is autologous blood, minus red blood cells, with higher-than-baseline concentrations of platelets prepared by centrifugal separation. Various growth factors, such as platelet-derived growth factor, vascular endothelial growth factor, and transforming growth factor β1 (TGF-β1), among others, are present. Current evidence suggests that PRP stimulates chondrogenesis and regeneration while increasing HA production and stabilizing angiogenesis.18,30 Compared with intra-articular HA or placebo controls, PRP injections in the knee appear to be superior for pain control and functional improvement during the first 6 months in the treatment of OA.23,41,49 At this time, more substantiated clinical data are required to determine the efficacy of PRP in the treatment of symptomatic OA. Certainly, there are less data to suggest that PRP can influence the natural history of an osteoarthritic knee. Rather, its mechanism of action is likely anti-inflammatory, which can alter the local intra-articular milieu of catabolic and anabolic growth factors and cytokines.33 Appropriate surgical management of OA is determined by specific patient symptoms, clinical and radiographic findings, circumstances, and expectations. While younger patients with isolated unicompartmental OA may benefit from a high tibial osteotomy or unicompartmental knee arthroplasty, patients with advanced, multiple compartmental OA are more likely to benefit from total knee arthroplasty. The routine use of arthroscopic debridement for the treatment of OA has been challenged recently by several randomized control studies demonstrating no significant difference between arthroscopic management and placebo in the treatment of knee OA.24,35 Although many nonsurgical and surgical treatment modalities improve pain and function in OA patients, none alter the natural history of the disease process. Recently, there has been increased focus on the potential role of stem cells in the management of OA. The following sections provide a brief overview on the different types of stem cells that can be used, with particular emphasis on the potential role of mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells.