Nontraditional Modification to Articular Cartilage
Biomechanical imbalance, trauma, and age-related degeneration often lead to chondral lesions, which may lead to overt osteoarthritis over time. Such cartilage pathology is frequently accompanied by persistent pain and loss of normal joint function. As a result, patients who suffer from biologically active articular cartilage lesions are often unable to function in high-level activities and may exhibit compromised activities of daily living. The limited potential for self-regeneration of hyaline cartilage has led to the emergence of new technologies to solve this difficult clinical problem. In the event that the chondral lesion remains superficial to the subchondral bone, repair relies on the proliferation of surrounding cells and cells within the synovium as lesions are not exposed to the cellular and protein components of circulating blood. Lesions that include the subchondral bone and expose the marrow cavity rely on components therein for regeneration and repair. Cartilage synthesized without exogenous intervention usually resembles type I fibrous cartilage, with inferior biomechanical properties when compared with native, hyaline cartilage replete with type II collagen.1
Treatment of arthritis and chondral lesions includes alleviation of pain and return of function through pharmacologic intervention and/or attempts at cartilage reparative, restorative, and reconstructive options.2 Systemic pharmacologic treatments for degenerative arthritis aim to reduce inflammation and decrease associated pain. Topical treatments include nonsteroidal anti- inflammatories such as diclofenac gels that isolate the pathologic joint, localizing treatment and decreasing the possibility of systemic side effects. Traditional injectables such as cortisone injections and viscosupplementation have been found to decrease pain for short and medium time periods. Corticosteroids have been shown to provide a 30 to 50% decrease in pain that is most evident in the first 4 weeks after treatment.3 Viscosupplementation with various formulations and molecular weights of hyaluronic acid has been shown to impart similar but longer-lasting results.4
It is our purpose to discuss the nontraditional and innovative nonsurgical treatments for articular cartilage pathology. Weight loss, physical therapy, oral anti- inflammatories, and corticosteroids are, at present, the standard of care for conservative treatment modalities for arthritis. The use of biologic injectables such as growth factors, platelet-rich plasma (PRP), autologous conditioned serum (ACS), and stem cell therapy is currently under investigation and will be the present focus. Although the clinical evidence supporting the use of these modalities is sparse, their potential is clear, as is the need for their continued development.
Growth Factors and Cytokines
Osteoarthritis is largely a cytokine-driven disease process. The synovial membrane, cartilage, and subchondral bone are all potential factors in cartilage degeneration as each is capable of producing large amounts of cytokines. A thorough understanding of the clinically relevant interactions between cytokines, mediators, growth factors, and mechanisms of action in this local environment is needed to ameliorate cartilage degeneration caused by the catabolic milieu present in osteoarthritis. Accompanying the increased interest in nontraditional treatment methods for articular cartilage disease is an increased interest in the use of cytokines as the basis for biological treatments such as PRP and ACS.
Growth factors are commonly defined as biologically active polypeptides that contribute to the regulation of growth and homeostasis of tissues throughout life.5,6 The use of growth factors such as transforming growth factor (TGF), fibroblast growth factor (FGF), and bone morphogenic (BMP) to influence cell differentiation and anabolism is a possible solution in the context of osteoarthritis.7–9 Recent basic science studies have shown an increasingly important role for growth factors in cartilage regeneration and have become the basis for the potential clinical benefits of modification of articular cartilage.9,10
TGF-β1 has been shown, in vitro, to stimulate the synthesis of extracellular matrix within cartilage, induce synovial proliferation, and increase mesenchymal stem cell (MSC) proliferation.11–14 Positive effects of TGF-β1 have also been documented in cartilage defects within rabbit models.15–19 Despite the positive effects of TGF-β1, safety concerns, specifically the presence of osteophytes and synovial fibrosis in murine and lapine studies, have limited extensive human testing.14,20 Albeit on a smaller scale, compared with TGF-β1, TGF-β3 has been shown to stimulate extracellular matrix (ECM) formation in animal models21–23 without these adverse effects.
BMP-2 is a close structural relative to both TGF-β1 and TGF-β3 and has been studied extensively in fracture care and spine surgery. The clinical success of BMP-2 in orthopedics has spurred basic science research investigating its potential effect on cartilage regeneration. In multiple studies, it has been shown in vitro to partially reverse dedifferentiated chondrocytes found in osteoarthritic models.24 In addition, BMP-2 stimulates the synthesis and turnover of extracellular matrix, and specifically that of proteoglycans and type II collagen. Augmentation of a microfracture model with BMP-2 has also been reported in a rabbit model. Although surgical intervention is beyond the present scope, it is valuable to note that BMP-2 may guide differentiating cells to produce more hyaline-like cartilage.25–27 Although the effects of BMP-2 on chondrocyte metabolism seem promising, synovial thickening, fibrosis, and, in some cases, osteophytes have been shown to develop after multiple injections.28 In addition, a recent animal study suggests temporal limitations to the use of BMP-2.29 Although the efficacy of BMP-2 seems promising, further studies are needed to develop the most efficacious dosing, timing, and route of administration.
BMP-7/OP-1 is the most investigated member of the TGF-β superfamily for its potential to regenerate articular cartilage. Not only does BMP-7 increase ECM synthesis, it decreases the activity of catabolic cytokines such as interleukin (IL-1), IL-6, IL-8, matrix matalloproteinase-1 (MMP-1), and MMP-7.30 BMP-7 expression has been shown to decrease with age. Although decreased BMP-7 expression is a factor in cartilage breakdown, BMP-7 continues to have autocrine effects for both anabolism and catabolism.31–34 Finally, although basic science studies suggest a beneficial effect from the administration of BMP-7, recent basic science and clinical literature has not shown a trend between endogenous levels of BMP-7 and higher symptomatic pain relief in patients with osteoarthritis.35 The efficacy of BMP-7 seems to be clear; however, the need to develop the proper dosing, timing, and route of administration remains uncertain.
Insulin-like growth factor-I (IGF-1) has been investigated within the context of cartilage metabolism in both native and pathologic states.30,36–39 IGF-1 has been shown to increase the anabolic response and decrease catabolism.40 In contrast to evidence found in BMP-7, IGF-1 shows a decreased responsiveness in aging and osteoarthritic cartilage.41,42 Although IGF-1 may not be a viable option alone, it may offer a synergistic effect in conjunction with other growth factors.36 Further studies are necessary to determine the optimal combination of growth factors.
Recent evidence suggests that platelet-derived growth factor (PDGF) has a possible place in cartilage repair based on its role in wound healing and stimulation of ECM proliferation in bone growth.43–46 Multiple animal studies have shown that PDGF has an excellent safety profile when used in isolation. PDGF has had an increasingly prominent role in research and media as in vivo use of PDGF remains largely within the context of PRP. PRP has been used successfully in various clinical situations and has drawn national attention as it has shown promising results for tendon healing.
Blood-Derived Products
Although growth factors show promise, they must be carefully synthesized and stored and are thus very expensive to produce. As evidenced above, they may also have a synergistic effect and would thus require varied concentrations of multiple growth factors, a practice that is not sanctioned by the U.S. Food and Drug Administration. Thus, there has been a recent resurgence in interest in the use of the body′s own combination of growth factors and cytokines using autologous blood as a medium from which to extract growth factor and cytokine-containing components such as platelets.
Autologous Conditioned Serum
Autologous conditioned serum (ACS) was developed in the mid-1990s and marketed under the name Orthokine (Arthrex, Inc., Naples, FL). It has been reported not only to be beneficial in the treatment of osteoarthritis, but also to be beneficial in rheumatoid arthritis, spinal disorders, and muscle injuries in humans.47–51 To prepare an ACS injection, human whole blood from the patient is incubated with medical-grade glass beads or spheres, exposed to chromium sulfate, and placed into a centrifuge to separate into the plasma with platelets.48 ACS is believed to be effective through its increased concentrations of cytokines and growth factors. Multiple studies have shown that the expression of IL-4, IL-10, IL-1Ra (receptor antagonist), fibroblastic growth factor-1, hepatocyte growth factor, and TGF-β1 are increased in human ACS. While there is an increase in these anti-inflammatory agents, there is no increase in proinflammatory cytokines-like IL-1β or TNF-α.47
In particular, IL-1Ra expression has been shown to increase as much as 140-fold in ACS. IL-1Ra is a competitive receptor antagonist of IL-1, a proinflammatory cytokine that triggers the destruction of hyaline cartilage and its matrix.48 Thus IL-1Ra may play a role in the clinical improvement of osteoarthritis patients injected with ACS. IL-1 has also been identified as being the major mediator of cartilage loss in osteoarthritis. Currently, it is not clear if all biologically active IL-1 receptors need to be blocked to have a significant impact on treating conditions such as osteoarthritis; however, it is known that other anti-inflammatory cytokines that are expressed in ACS also affect IL-1 receptor signaling.48 In gene therapy studies, it was found that IL-1Ra decreases synovial effusion, gross articular cartilage erosion, and synovial membrane vascularity as compared with placebo-treated joints.47
To induce the de novo production of IL-1Ra, aspirated venous blood is incubated with borosilicate glass spheres in a syringe. The anti-inflammatory cytokines, which are produced by peripheral blood leukocytes, accumulate and are recovered within the serum. The cytokine concentrations do vary between individual samples, and their synergistic action contributes to the effects.48 After centrifugation, ACS can be injected into the osteoarthritic area in a series of six intraarticular injections twice a week for 3 weeks.47,52
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