Mi SciELO
Servicios Personalizados
Revista
Articulo
Indicadores
-
Citado por SciELO
-
Accesos
Links relacionados
-
Citado por Google
-
Similares en SciELO
-
Similares en Google
Compartir
Revista de la Sociedad Española del Dolor
versión impresa ISSN 1134-8046
Rev. Soc. Esp. Dolor vol.28 no.5 Madrid sep./oct. 2021 Epub 17-Ene-2022
https://dx.doi.org/10.20986/resed.2021.3903/2021
REVIEW
A new paradigm for the treatment of knee osteoarthritis: the role of hyaluronic acid, platelet-rich plasma (prp) and ozone in the modulation of inflammation: a review
1Servicio de Medicina Física y Rehabilitación. Hospital Universitario Santa Cristina. Madrid, España
2Servicio de Farmacia Hospitalaria. Hospital Universitario Santa Cristina. Madrid, España
3Servicio de Laboratorio Clínico. Hospital Universitario Santa Cristina. Madrid, España
CONTEXT
Osteoarthritis (OA) is the most common cause of arthritis. OA has a direct impact on quality of life to the extent that it is the eleventh global contributor to disability worldwide. The burden of the disease in terms of cost is such that an estimated 4 million people are affected in Spain, involving an annual cost of EUR 4378 million per year, or 0.5 % of gross domestic product 1.
OA is a major public health problem. In people over 60 years of age, 13% report symptomatic knee OA; in people over 70 years of age, 27% have radiological signs of OA; and in people over 80 years of age, 44% have radiological signs and clinical symptoms 2.
Typically, OA was considered a "wear and tear" disease. However, metabolic and inflammatory factors are new pathogenic factors. In fact, some authors are redefining OA as a "low-grade chronic inflammation" disease 3. Therefore, there is a paradigm shift for OA, from biomechanical to inflammatory theory 2,3.
Biomechanical theory states that OA is a mechanically induced disease. Joint cartilage is overloaded as a result of poor alignment, poor mechanics, and load or impact. This overload compromises the cartilage support structure, causing it to soften and degrade. Once the cartilage softens, the bone beneath it hardens and the joint breaks. If the overload is not modified, the OA will progress. Once the elasticity of the subchondral bone disappears, the progressive destruction of cartilage and bone leads to the formation of osteophytes to increase the surface area, thus decreasing the load. Finally, the progression of the joint deformity moves the weight support axis to the opposite compartment and further joint destruction continues. Total knee arthroplasty is indicated as a final treatment at this stage 4.
Inflammatory and immune theory states that in cartilage, cells are exposed to wear forces within the extracellular matrix (ECM) and on the surface of the joint. As a result, ECM is destroyed, releasing inflammatory cytokines such as IL-6, IL-8, matrix metalloproteases (MMP), leukemia inhibitory factor (LIF), and oncostatin M (OSM). These danger signals trigger second messengers, worsening the inflammatory environment. Furthermore, cartilage senescence induces apoptosis and inflammatory responses are enhanced. These cells and inflammatory signals incite an inflammatory cascade that surpasses the innate healing response, leading to a catabolic state that produces more cartilage destruction (4).
The ECM can be destroyed by inflammation or by apoptosis mechanisms, which are mediated by immune or inflammatory responses 4. In this inflammatory environment, by acting on well-known signaling cascades, cell and protein signaling could promote favorable healing responses (4). Mesenchymal stem cells reduce inflammation, fight apoptosis (cell death), self-replicate and differentiate across multiple tissues. Platelet-rich plasma (PRP) contains nearly 1200 proteins, including growth factors and anti-inflammatory cytokines 4. They block inflammation and stimulate cartilage healing 4.
The new paradigm of the management of knee OA is based on cell signaling treatments, based on cellular and protein components. Both components are expected to interact with resident stem cells, inflammatory cells, and immune cells to combat the inflammatory environment of the joint and regenerate damaged tissue 4.
Today there is no cure for OA. The goal of short-term treatment is to decrease pain and regain the quality of life and function of patients, and in the long term to slow/stop disease progression 1. New treatment options for the management of knee osteoarthritis in the form of intra-articular infiltrations include hyaluronic acid (HA), glucocorticoids, analgesics, and unproven complementary therapies, such as platelet-rich plasma (PRP) 5 or even ozone 1. However, the good results obtained with biological drugs that fight inflammation (such as in rheumatoid arthritis), based on an approach to treating only one therapeutic target, have not been found for the management of knee OA 5.
We pose that a multi-target approach would be beneficial for the treatment of knee OA because many signaling pathways and inflammatory mediators are involved in the origin of knee OA 4.
HA, PRP and ozone act on the modulation of inflammation through different mediators and signaling pathways 1,4,5, therefore these treatment options could be considered, taking into account their multitarget profile, for the management of knee OA in the near future.
The objective of the present study is to review the pathophysiology of OA, focusing mainly on the inflammatory mechanism, the signaling pathways involved and potential treatment targets, and to pose to HA, PRP and ozone as multi-target treatment options for the management of knee osteoarthritis.
STATE OF THE ART
Pathogenesis and diagnosis of osteoarthritis
With aging, the cartilage undergoes histological changes and degradation. As a result, catabolic enzymes (MMP1, MMP10, MMP13, IL-1α, IL-6, IL-7, IL-8), glycation end-products, reactive oxygen species (ROS), apoptotic and necrotic cells are released and the ECM is decomposed 6. ROS, inflammatory cytokines, and catabolic proteins are involved in the aging process of articular cartilage 6.
Acting on mesenchymal stem cells (MSC) is necessary for the repair of cartilage. Typically, some stimuli such as TGF-β (transforming growth factor β), IGF-1 (insulin-like growth factor 1), mechanical loading and hypoxia induce the differentiation of chondroblasts into specific chondrocytes and produce elastic cartilage, hyaline cartilage, and fibrocartilage 6. As a result, articular cartilage and collagen type II, IX and X are produced 6.
OA occurs because of modifiable risk factors (obesity, occupation, injury, physical activity, sports, and diet) and non-modifiable risk factors (sex, age, genetics, and hormones). OA presents as a group of signs and symptoms, including pain, swelling, joint stiffness, and muscle weakness 7.
According to EULAR (European League Against Rheumatism), at least 3 symptoms and 3 clinical and laboratory signs must be present for the diagnosis of OA. Clinical signs and symptoms include joint pain, stiffness, loss of function, crepitus, limitation of movement, and bone enlargement. Laboratory signs include ESR (erythrocyte sedimentation rate) less than 40 mm/h, rheumatoid factor less than 1:40, and synovial fluid with leukocytes less than 2000 cells/uL 8.
OA is classified in 4 degrees according to Kellgren and Lawrence (KL): In grade 1 there is a suspicion of narrowing of the joint space and possible overgrowth of osteophytes; grade 2 shows possible narrowing of the joint space and defined osteophytes; grade 3 represents definitive sclerosis and narrowing of the minimum joint space and possible bone irregularity; grade 4 is characterized by large osteophytes, significant narrowing of the minimum joint space, major sclerosis, and some bone irregularity 8.
The diagnosis of OA is clinical and radiological. Unfortunately, the initiation of OA occurs before the radiological diagnosis is made. At this stage, the x-ray is unable to detect early stages of OA. Early diagnosis will allow us to establish a preventive treatment to slow or halt cartilage destruction 9.
A biomarker is a quantifiable marker of a biological process. In OA, a biomarker should be involved in osteogenesis and inflammation. A biomarker in OA quantifies the osteogenic or inflammatory changes observed in serum, urine, or synovial fluid; and this change, either in tissue growth or degradation, could even precede radiographic changes 9.
For knee osteoarthritis, inflammatory and non-inflammatory biomarkers are considered. Non-inflammatory biomarkers include metabolic collagen biomarkers (CTX-I [C-terminal telopeptide], CTX-II), metabolic biomarkers other than collagen (proteoglycans, aggrecanases [chondroitin sulfate, keratan sulfate], non-aggrecanases [hyaluronic acid, osteocalcin, osteopontin, folastine]. Inflammatory biomarkers are divided into pro-inflammatory and anti-inflammatory. Proinflammatory biomarkers include adipokines (leptin, adiponectin, visfatin, and resistin), interleukins (IL-1β, IL-6, IL-15, IL-17, IL-18), chemokines (TNF-α), C-reactive protein (CRP), ESR and uric acid. Anti-inflammatory biomarkers include cytokines such as IL-4, IL-7, IL-8, IL-10, and IL-13 9.
The pathophysiology of OA is very complex. In knee osteoarthritis there is an imbalance between anabolic and catabolic factors. Catabolic factors include inflammatory cytokines (IL-1β, IL-6, IL-15, IL-17, IL-18, TNF-α, LIF]) and proteolytic enzymes (MMP-1, MMP3 and aggrecanases [ADAMTs]). Anabolic factors include anti-inflammatory cytokines (IL-4, IL-10) and anabolic cytokines (TGF-β, IGF-1, FGF-18 [fibroblast growth factor] and PDGF [platelet-derived growth factor]) 10. Inflammatory and catabolic factors produce an imbalance that leads a healthy joint to develop knee OA (Figure 1) 11).
![](/img/revistas/dolor/v28n5//1134-8046-dolor-28-05-00282-gf2.jpg)
MMP: Matrix mineral metalloproteases. ADAM: disintegrin and metalloprotease. ADAMTS: disintegrin and metalloprotease with thrombospondin motifs. NO: Nitric oxide. TNF-α: Tumor necrosis factor α. iNOS: inducible nitric oxide synthase. COX-2: Cyclooxygenase-2. CXCL: Chemokine receptor. CCL: Chemokine ligand. CRP: C-reactive protein. ESR: Erythrocyte sedimentation rate. TGF-β: Transforming growth factor β. HGF: Hepatocyte growth factor. VEGF: Vascular endothelial growth factor. EGF: Endothelial growth factor. IGF-1: Insulin growth factor 1. HDGF: Hepatocyte-derived growth factor. TIMPS: tissue inhibitor of metalloproteases. NF-Кβ: Nuclear factor Кβ
Fig. 1 Osteoarthritis is the result of an imbalance between anabolic and catabolic factors where pro-inflammatory cytokines and catabolic chemokines predominate over anti-inflammatory cytokines and anabolic chemokines.
Leptin is an adipokine with an inflammatory effect. An increase in body weight and an expansion of white adipose tissue lead to an increase in mechanical load; then, cartilage degradation is the end result, which triggers the development of OA. Furthermore, leptin derived from adipose tissue (overproduction in obese patients) is related to the deregulation of osteoblasts in subchondral bone tissue, leading to joint wear and tear damage. In addition, leptin releases pro-inflammatory cytokines derived from adaptive and innate immune cells, creating an inflammatory medium that favors cartilage and OA destruction 12.
In addition to leptin, other adipokines, such as visfatin, produce ROS and pro-inflammatory cytokines cause inflammation and cartilage degradation 13.
Obesity and metabolic syndrome are associated with low-grade chronic inflammation, leading to joint injury, pain, and disability. Metabolic syndrome/obesity releases IL-1β, IL-6, PGE2, TNF-α and adipokines. Catabolic factors produce synovitis, subchondral sclerosis, and joint injury 13.
Denoble suggests that uric acid is related to OA degradation through the inflammasome (NLRP3) 14. OA joints release nuclear agents that promote the crystallization of the urate. As OA progresses, cell death releases uric acid. In hyperuricemic patients, uric acid spreads from the blood to the synovial fluid in the joint. These diffusion mechanisms or apoptosis produce subacute inflammation and promote the progression of OA by activation of the inflammasome pathway 14. Similarly, Mc Alister states that NLRP3 (inflammasome) could be activated via the NF-Кβ pathway [nuclear factor-Кβ] or by caspases, releasing inflammatory cytokines (IL-1β and IL-18), leading to chronic inflammation, favoring OA progression 15. Wehmeyer states that OA and rheumatoid arthritis (RA) share the RankL [receptor activator of nuclear factor Kappa-β ligand] or NF-Кβ signaling pathway and that blocking this pathway would be a valid treatment option 16.
Pulsatelli states that OA is not only a disease of cartilage, but of subchondral bone and synovial tissue 17. Several signaling pathways act on chondrocytes, leading to cartilage alteration and bone formation in OA 16. Blocking these signaling pathways could prevent the progression of OA 17.
Kennedy states that inflammatory cytokines (IL-1β, IL-6, TNF-α) can act in several signaling pathways. They can release ROS and act on cartilage degradation. They may also act on MMPs in the matrix leading to the degradation of type X collagen. Inflammatory cytokines can also act on the RANKL membrane ligand, activating the NF-Кβ nuclear pathway, acting on the transcription factor SOX-9 (chondrogenic protein) and COX-2 (cyclooxygenase), degrading type II collagen 18.
Mobasheri states that not only the pathogenesis of OA is complex, but the phenotypes of OA are varied 19. There are several phenotypes in osteoarthritis (bone, metabolic, subchondral, aging-associated, cartilage-associated, trauma injury-associated, synovitis-associated, etc.); metabolism is involved in several of them, and they also share similar signaling pathways 19. In this regard, Berembaum suggests that the metabolic syndrome releases inflammatory mediators into the blood, which are harmful to the articular tissues and initiate or perpetuate this process. Once arthritic cells become active, they release inflammatory mediators in the joint and blood, amplifying low-grade inflammation and accelerating other low-grade chronic systemic diseases 20. Therefore, metabolic syndrome not only worsens OA, but also acute trauma, aging, and crystal diseases, releasing systemic mediators of inflammation that would exacerbate diseases such as Alzheimer's disease, arteriosclerosis, or acute myocardial infarction 20. In summary, OA is affected by low-grade chronic inflammation as it occurs in metabolic syndrome (obesity, insulin resistance, lipid abnormalities, hypertension), and the development of OA contributes to low-grade chronic inflammation through the systemic effects of inflammatory mediators derived from OA, inducing and accelerating other chronic diseases (Alzheimer's disease, stroke, myocardial infarction) 20.
Altered body composition, altered metabolites, and inflammation derived from fatty tissue and synovial tissue release inflammatory mediators that worsen OA. Abnormal dietary factors and dysfunctional fatty tissue produce and increase adipokines leading to an increased risk of OA development due to the release of inflammation mediators (complement, CRP, cytokines) 21.
Guisasola and Ortiz demonstrated an increase in inflammatory cytokines (IL-1β, IL-6, TNF-α and thermal shock proteins) in acute polytrauma 22. Perpetuation of an acute aggression leading to chronic inflammation may induce post-traumatic OA. Lieberthal states that resolving inflammation with specific cytokine blocking would solve the problem 23.
Single target treatment
Since there is no cure for OA, there are many therapeutic targets under study for the treatment of OA 24. The standard treatment in advanced OA is total replacement arthroplasty, with an efficiency of 95% at 10 years and 90% at 15 years 1. However, this approach involves risks and complications 1.
Many targets are proposed as therapeutic options for the management of early OA. Therapeutic targets include: A) mitochondrial function regulators, b) nutraceuticals, c) apoptosis regulators, d) iNOS [inducible nitric oxide synthase] inhibitors, e) analgesics and NSAIDs [non-steroidal anti-inflammatory drugs], f) MMP inhibitors, g) pro-inflammatory cytokine blockers, h) herbal medications, i) bone density conservation agents, j) bisphosphonates and k) strontium ranelate 24.
Nitric oxide inhibitors and antioxidants
Nitric oxide inhibitors and antioxidants are able to modulate inflammation, but are not useful in the management of OA 25,26.
Nutraceuticals
Curcumin could slow the progression of OA and decrease OA-related pain symptoms in the post-traumatic OA mouse model. Unfortunately, these findings have not yet been demonstrated in humans 27).
Uric acid reducing agents
OA, rheumatoid arthritis, and gout share similar signaling pathways. Unfortunately, medications lowering uric acid levels (such as allopurinol or uricosuric medications) do not lower the risk of total knee replacement 28.
Colchicine is an antimitotic and anti-inflammatory drug. In a recent study, colchicine showed a decrease in inflammation and biomarkers of bone turnover (both factors related to progression and severity in OA patients). However, in the long term (16-week follow-up), colchicine was not able to reduce the symptoms of OA of the knee 29).
Biological therapy
Biologic therapy targeting specific cytokines or interleukins (such as anakinra, infliximab, etanercept, adalimumab, tocilizumab, or denosumab) has shown to be effective in treating rheumatoid arthritis (RA). Unfortunately, biological drugs have not demonstrated their efficacy in the treatment of OA, there is no disease-modifying effect on the progression of OA 20. Biological drugs target inflammatory processes, but their excellent results observed in RA have not been successfully translated into OA 30.
Blocking TNF-α
TNF-α is a proinflammatory cytokine that targets chondrocytes causing cartilage loss 30. Infliximab showed initial tolerability in early exploratory trials, but was not effective in the treatment of knee osteoarthritis (20,30). Etanercept showed effectiveness in pain relief, but the effect lasted only 4 weeks 30. Adalimumab was safe and improved symptoms in OA, but has not progressed in the management of knee OA 30.
Multi-target treatment
Exercise and weight loss
Exercise increases the anti-inflammatory IL-10 at the perisynovial and intra-articular site of the knee 31. Weight loss decreases IL-6 and leptin and improves pain, function, quality of life, muscle strength, and endurance in patients with symptomatic knee osteoarthritis (32). Exercise and weight loss can act as a multimodal approach decreasing inflammatory cytokines and adipokines (IL-6, leptin) and increasing anti-inflammatory cytokines (IL-10) 31,32.
Hyaluronic acid
Hyaluronic acid (HA) is a component of synovial fluid and is responsible for its viscoelasticity. In OA, the concentration and molecular weight of HA decrease, reducing the mechanical protection of the joint. Intra-articular infiltration of HA may restore the elasticity of synovial fluid, adding shock absorption, lubrication, and joint protection. In addition, HA increased the proliferation of chondrocytes and decreased their apoptosis, slowing the destruction and progressive narrowing of the joint space, which is related to OA, acting as a chondroprotective agent. Anti-inflammatory and analgesic effects of HA have also been reported in the literature 33).
Nichols has stated that HA can act on ECM degradation and inflammation and pain 34. Depending on the molecular weight, HA may act on different cytokines of degradation and inflammation 34.
In the Nichols study, low molecular weight (LMW) HA inhibited MME (macrophage metalloelastase) and MMP-10 responsible for ECM degradation 34. Low molecular weight (LMW) HA also inhibited CCL-2 (chemokine ligand), CCL-3, CCL-4, CXCL-2 (chemokine receptor), CXCL-9, CXCL-10, and IL-12, responsible for the development of inflammation/pain 34. High molecular weight (HMW) HA inhibited ADAM-17 (disintegrin and metalloprotease), ADAMTS-4 (disintegrin and metalloprotease with thrombospondin motifs), ADAMTS-5 and MMP-1, MMP-2, MMP-3, related to ECM degradation. High molecular weight (HMW) HA also inhibited IL-6, NF-Кβ (nuclear factor), phospho-Akt, phospho-JNK (c-Jun N-terminal kinase) and TLR-4 (toll-like receptor), cytokines related to the presence of pain and inflammation. Both LMW HA and HMW HA can act on MMP-9 and MMP-13, inhibiting ECM degradation. LMW HA and HMW HA inhibit IL-1β, IL-8, TNF-α, CCL-5, iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase), responsible for the presentation of pain and inflammation 34 (Table 1).
Table I Multitarget profile of hyaluronic acid, platelet-rich plasma and ozone with stimulation (↑) and inhibition (↓) effects.
![](/img/revistas/dolor/v28n5//1134-8046-dolor-28-05-00282-gt2.jpg)
↓ = inhibition. ↑ = stimulation. MMMP: Matrix mineral metalloproteases. ADAM: disintegrin and metalloprotease. ADAMTS: Disintegrin and metalloprotease with thrombospondin motifs. NO: Nitric oxide. TNF-α: Tumor necrosis factor α. INOS: Nitric oxide synthase inducible. COX-2: Cyclooxygenase-2. CXCL: Chemokine receptor. CCL: Chemokine ligand. CRP: C-reactive protein. ESR: Erythrocyte sedimentation rate. TGF-β: Transforming growth factor β. HGF: Hepatocyte growth factor. VEGF: Vascular endothelial growth factor. EGF: Endothelial growth factor. IGF-1: Insulin growth factor 1. HDGF: Hepatocyte-derived growth factor. TIMPS: tissue inhibitor of metalloproteases. NF-Кβ: Nuclear factor Кβ.
HA acts on the symptomatic (pain and inflammation) and disease-modifying (ECM degradation) effects in OA, so HA may be a multi-target drug and a valid option for the treatment of knee OA 34.
Platelet-rich plasma (PRP)
Platelet-rich plasma is an autologous product that, by centrifugation, raises the platelet level severalfold compared to that observed in blood serum 30. PRP has several mediators communicating with the joint cells 30.
Some authors state that PRP contain 300 molecules or proteins identified by proteomics in the α-granules 35,36, while others argue that PRP contain nearly 800 proteins 37 and even 1200 proteins, including growth factors (GF) and anti-inflammatory cytokines 4. These GF and cytokines can inhibit inflammation and stimulate cartilage healing 4,30,35,36,37.
Kennedy states that PRP modulates inflammation by inhibiting IL-1β and TNF-α. PRP promotes cell proliferation and renewal by stimulating TGF-β (transforming growth factor β) and HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), EGF (endothelial growth factor), IGF-1 and PDGF (platelet-derived growth factor) 18. In fact, HGF inhibits NF-Кβ and decreases NO (nitric oxide) synthesis 18. Ornetti reported that PRP inhibits the NF-Кβ pathway through HGF 37. PRP is also able of inhibiting the NF-Кβ pathway via IGF-1 37. HGF limits the inflammatory response within the synovial membrane 37. Demange stated that PRP can attenuate pro-inflammatory cytokines such as NF-Кβ and IL-1 38 (Table I).
PRP can act on different cytokines and signaling pathways, modulating inflammation and decreasing cartilage degradation and promoting cartilage healing 4,30,35,36,37,38. The multitarget profile of PRP makes this therapy a promising alternative for the treatment of knee osteoarthritis.
Ozone (O 2 -O 3 )
Ozone (O2-O3) modulates inflammation and pain in patients with knee OA 41. In addition, the anabolic effect of ozone (O2-O3) could play an important role in modifying the natural history of OA, as recently reported in a clinical case 39,40.
Recently, Fernandez-Cuadros et al. reported the immunomodulatory and anabolic properties of ozone (O2-O3) through the positive regulation of anti-inflammatory cytokines (IL-4, IL-10), growth factors (TGF-β, IGF-1), stem cells and inhibitory regulation of inflammatory and catabolic cytokines (MMPS, NO, PGE2] 1,40 (Table I).
Manoto et al. stated that ROS activate the NF-Кβ pathway leading to cartilage apoptosis. The authors have also shown that ozone could block the NF-Кβ pathway, decreasing inflammatory cytokines such as IL-1β, IL-6, TNF-α and COX-2, considering ozone (O2-O3) as a promising option for cartilage growth in patients with knee osteoarthritis 12. Fernandez-Cuadros has found that intra-articular ozone is capable of reducing CRP, ESR (erythrocyte sedimentation rate) and uric acid, recognized as biomarkers of inflammation in patients with OA of the knee, confirming that ozone modulates inflammation 41,42 (Table I).
From previous research, ozone (O2-O3) could be expected to play a role in the treatment of patients with knee OA (40,43).
RESULTS
This is the first article reviewing the role of inflammation as the leading cause in OA pathogenesis and suggests HA, PRP and ozone as potential treatment options due to their multitarget profile in inflammation modulation.
The pathophysiology of OA is very complex. Many signaling pathways are involved. Proteolytic molecules and inflammatory mediators are involved in the initial progression of the disease 2. OA was classically defined as a "wear and tear" disease, but now biochemical, biomechanical, metabolic, and genetic variables are considered key factors for disease progression 30, so the paradigm has shifted from biomechanical to inflammatory theory 3.
The therapeutic objectives in OA are: a) to slow the degradation-inflammation cycle, b) to inhibit inflammation mediators, c) to decrease catabolic chemokines, and d) to stimulate anabolic chemokines 35.
In this review, drugs that have a single-target treatment profile, including biological therapies (such as anakinra [anti IL-1β] or infliximab, etanercept, adalimumab [anti-TNF-α], tocilizumab [anti IL-6] and even denosumab [RANKL-A]), which have shown to be effective in treating RA by inhibiting specific inflammatory cytokines, have not shown to be equally effective in the treatment of knee OA 20.
For the treatment of knee osteoarthritis, recognized guidelines are established by the ACR (American College of Rheumatology), OARSI (Osteoarthritis Research Society International), EULAR and AAOS (American Academy of Orthopaedic Surgeons) 33. However, none of the clinical guidelines has yet included PRP or ozone as treatment options 30,33.
In the case of the HA, there is controversy over its use. The AAOS (2013 recommendation) and NICE (2014 recommendation of the National Institute for Health and Care Excellence) do not support its use; while OARSI (2014 recommendation) and ACR (2012 recommendation) are inconclusive regarding the use of HA 30. There is only one systematic review that has stated that intra-articular treatments showed the greatest effect on the management of knee OA, including PRP and HA with a molecular weight larger than 1500 kDa 44.
An updated meta-analysis and review published separately by Nori-Zadehh et al. and Vazquez et al. have defined ozone (O2-O3) as a valid option for the management of knee OA due to its effectiveness in pain management 45,46.
Three recent meta-analyzes (Chang 2013, Khoshbin 2013, Tietze 2014) have indicated that PRP offers better results compared with HA or corticosteroids, and the effect remains for at least 6 months 2. Ornetti and Andia, in two recent reviews, reported that PRP has a role in the treatment of knee OA because of its anti-inflammatory and regenerative properties and the clinical benefits have been confirmed in randomized and non-randomized controlled trials 36,37.
Zamboni has stated that AH and PRP can promote regeneration and reduce inflammation 47). HMW HA (50-120 kDa) added to PRP (combination infiltrate) reduces cytokines and chemokines responsible for OA progression 48. The combination of intra-articular injections of HA and PRP may decrease immune system-related cells and may recover cartilage degradation and may repair meniscus tears (49). In addition, HA has been shown to increase GF production if added simultaneously to PRP infiltration, reducing the time needed for healing. The combination of PRP plus HA enhances the release of TGF-1 and PDGF, favoring the healing effect 49.
In this review, HA, PRP and ozone have shown to have anti-inflammatory, immunomodulatory and regenerative properties due to their multitarget profile.
Three recent meta-analyzes confirm the usefulness of PRP and HA in the management of OA. Chevalier et al., in a meta-analysis reviewing 42 clinical trials, found that HA is more effective than corticosteroids in the management of OA 50. Tan et al, in a meta-analysis of 26 randomized and controlled studies, found that PRP is more effective than HA in the management of OA, although both treatments showed the same safety profile 51. Finally, Han et al., in a meta-analysis including 43 trials, found that HA demonstrated better outcomes than PRP in the treatment of knee OA 52).
For all of the above reasons, we pose HA, PRP and ozone as drugs with a multitarget profile for the management of knee OA, as has been described in this review.
CONCLUSIONS
OA is a complex pathophysiology disease involving cartilage, subchondral bone, and synovial tissue. New studies suggest that inflammatory mechanisms are involved in the pathogenesis of OA, even more than biomechanical factors, to the extent that this review has proposed a paradigm shift. The OA has no definitive cure today. The aim of treatment is to interrupt the vicious cycle of inflammation-degradation by blocking specific inflammatory and catabolic pathways. The option to treat a single target that blocks a single signaling pathway has not produced significant results in the treatment of knee OA, as seen in the treatment of rheumatoid arthritis. In addition to exercise and weight loss, the multi-target profile of ozone, PRP, and HA offer a promising alternative for the management of knee OA, as these alternatives may act on inflammatory cytokines and catabolic chemokines, and may stimulate anabolic chemokines and anti-inflammatory cytokines, as described above. Clinical guidelines may consider these medications for the treatment of knee osteoarthritis, given the biological properties described in this review.
REFERENCES
1. Fernández-Cuadros ME, Pérez-Moro OS, Albaladejo-Florín MJ. Ozone fundamentals and effectiveness in knee pain: Chondromalacia and knee Osteoarthritis. Germany: Lambert Academic Publishing; 2016. [ Links ]
2. Richards MM, Maxwell JS, Weng L, Angelos MG, Golzarian J. Intra-articular treatment of knee osteoarthritis: from anti-inflammatories to products of regenerative medicine. Phys Sportsmed. 2016;44(2):101-8. DOI: 10.1080/00913847.2016.1168272. [ Links ]
3. Mobasheri A, Batt M. An update on the pathophysiology of osteoarthritis. Ann Phys Rehabil Med. 2016;59(5-6):333-9. DOI: 10.1016/j.rehab.2016.07.004. [ Links ]
4. Yeargan A. The Basis for Autologous signaling cell treatment for Osteoarthritic knee pain: Immunologic and Stem Cell signaling Basics. December, 2017. DOI 10.1314/RG.2.2.11757.69604. [ Links ]
5. Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT Jr. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol. 2019;15(2):77-90. DOI: 10.1038/s41584-018-0123-4. [ Links ]
6. Krajewska-Wlodarczyk M, Owczarczyk-Saczonek A, Placek W, Osowski A, Wojtkiewicz J. Articular Cartilage Aging-Potential Regenerative Capacities of Cell Manipulation and Stem Cell Therapy. Int J Mol Sci. 2018;19(2):623. DOI: 10.3390/ijms19020623. [ Links ]
7. Manoto SL, Maepa MJ, Motaung SK. Medical ozone therapy as a potential treatment modality for regeneration of damaged articular cartilage in osteoarthritis. Saudi J Biol Sci. 2018;25(4):672-9. DOI: 10.1016/j.sjbs.2016.02.002. [ Links ]
8. Lespasio MJ, Piuzzi NS, Husni ME, Muschler GF, Guarino A, Mont MA. Knee Osteoarthritis: A Primer. Perm J. 2017;21:16-183. DOI: 10.7812/TPP/16-183. [ Links ]
9. Gögebakan B, Izmirli M, Okuyan HM, Ataç L. Biomarkers for Early Diagnosis of Osteoarthritis. In: Osteoarthritis. SM dbooks; 2016. [ Links ]
10. Richards MM, Maxwell JS, Weng L, Angelos MG, Golzarian J. Intra-articular treatment of knee osteoarthritis: from anti-inflammatories to products of regenerative medicine. Phys Sportsmed. 2016;44(2):101-8. DOI: 10.1080/00913847.2016.1168272. [ Links ]
11. Manoto SL, Maepa MJ, Motaung SK. Medical ozone therapy as a potential treatment modality for regeneration of damaged articular cartilage in osteoarthritis. Saudi J Biol Sci. 2018;25(4):672-9. DOI: 10.1016/j.sjbs.2016.02.002. [ Links ]
12. Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA, et al. Obesity, Fat Mass and Immune System: Role for Leptin. Front Physiol. 2018 Jun 1;9:640. DOI: 10.3389/fphys.2018.00640. [ Links ]
13. Courties A, Gualillo O, Berenbaum F, Sellam J. Metabolic stress-induced joint inflammation and osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1955-65. DOI: 10.1016/j.joca.2015.05.016. [ Links ]
14. Denoble AE, Huffman KM, Stabler TV, Kelly SJ, Hershfield MS, McDaniel GE, et al. Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation. Proc Natl Acad Sci U S A. 2011;108(5):2088-93. DOI: 10.1073/pnas.1012743108. [ Links ]
15. McAllister MJ, Chemaly M, Eakin AJ, Gibson DS, McGilligan VE. NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarthritis Cartilage. 2018;26(5):612-9. DOI: 10.1016/j.joca.2018.02.901. [ Links ]
16. Wehmeyer C, Pap T, Buckley CD, Naylor AJ. The role of stromal cells in inflammatory bone loss. Clin Exp Immunol. 2017;189(1):1-11. DOI: 10.1111/cei.12979. [ Links ]
17. Pulsatelli L, Addimanda O, Brusi V, Pavloska B, Meliconi R. New findings in osteoarthritis pathogenesis: therapeutic implications. Ther Adv Chronic Dis. 2013;4(1):23-43. DOI: 10.1177/2040622312462734. [ Links ]
18. Kennedy MI, Whitney K, Evans T, LaPrade RF. Platelet-Rich Plasma and Cartilage Repair. Curr Rev Musculoskelet Med. 2018;11(4):573-82. DOI: 10.1007/s12178-018-9516-x. [ Links ]
19. Mobasheri A, Rayman MP, Gualillo O, Sellam J, van der Kraan P, Fearon U. The role of metabolism in the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2017;13(5):302-11. DOI: 10.1038/nrrheum.2017.50. [ Links ]
20. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013;21(1):16-21. DOI: 10.1016/j.joca.2012.11.012. [ Links ]
21. Wang X, Hunter D, Xu J, Ding C. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage. 2015;23(1):22-30. DOI: 10.1016/j.joca.2014.10.002. [ Links ]
22. Guisasola MC, Ortiz A, Chana F, Alonso B, Vaquero J. Early inflammatory response in polytraumatized patients: Cytokines and heat shock proteins. A pilot study. Orthop Traumatol Surg Res. 2015;101(5):607-11. DOI: 10.1016/j.otsr.2015.03.014. [ Links ]
23. Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1825-34. DOI: 10.1016/j.joca.2015.08.015. [ Links ]
24. Mobasheri A. The future of osteoarthritis therapeutics: targeted pharmacological therapy. Curr Rheumatol Rep. 2013;15(10):364. DOI: 10.1007/s11926-013-0364-9. [ Links ]
25. Mazzetti I, Grigolo B, Pulsatelli L, Dolzani P, Silvestri T, Roseti L, et al. Differential roles of nitric oxide and oxygen radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis. Clin Sci (Lond). 2001;101(6):593-9. DOI: 10.1042/CS20010030. [ Links ]
26. Davies CM, Guilak F, Weinberg JB, Fermor B. Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. Osteoarthritis Cartilage. 2008;16(5):624-30. DOI: 10.1016/j.joca.2007.09.012. [ Links ]
27. Zhang Z, Leong DJ, Xu L, He Z, Wang A, Navati M, et al. Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model. Arthritis Res Ther. 2016;18(1):128. DOI: 10.1186/s13075-016-1025-y. [ Links ]
28. Kuo CF, Chou IJ, See LC, Chen JS, Yu KH, Luo SF, et al. Urate-lowering treatment and risk of total joint replacement in patients with gout. Rheumatology (Oxford). 2018;57(12):2129-39. DOI: 10.1093/rheumatology/key212. [ Links ]
29. Leung YY, Haaland B, Huebner JL, Wong SBS, Tjai M, Wang C, Chowbay B, Thumboo J, Chakraborty B, Tan MH, Kraus VB. Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial. Osteoarthritis Cartilage. 2018;26(5):631-40. DOI: 10.1016/j.joca.2018.01.026. [ Links ]
30. Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT Jr. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol. 2019;15(2):77-90. DOI: 10.1038/s41584-018-0123-4. [ Links ]
31. Helmark IC, Mikkelsen UR, Børglum J, Rothe A, Petersen MC, Andersen O, et al. Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial. Arthritis Res Ther. 2010;12(4):R126. DOI: 10.1186/ar3064. [ Links ]
32. Miller GD, Jenks MZ, Vendela M, Norris JL, Muday GK. Influence of weight loss, body composition, and lifestyle behaviors on plasma adipokines: a randomized weight loss trial in older men and women with symptomatic knee osteoarthritis. J Obes. 2012;2012:708505. DOI: 10.1155/2012/708505. [ Links ]
33. Wehling P, Evans C, Wehling J, Maixner W. Effectiveness of intra-articular therapies in osteoarthritis: a literature review. Ther Adv Musculoskelet Dis. 2017;9(8):183-96. DOI: 10.1177/1759720X17712695. [ Links ]
34. Nicholls MA, Fierlinger A, Niazi F, Bhandari M. The Disease-Modifying Effects of Hyaluronan in the Osteoarthritic Disease State. Clin Med Insights Arthritis Musculoskelet Disord. 2017;10:1179544117723611. DOI: 10.1177/1179544117723611. [ Links ]
35. Moussa M, Lajeunesse D, Hilal G, El Atat O, Haykal G, Serhal R, Chalhoub A, Khalil C, Alaaeddine N. Platelet rich plasma (PRP) induces chondroprotection via increasing autophagy, anti-inflammatory markers, and decreasing apoptosis in human osteoarthritic cartilage. Exp Cell Res. 2017;352(1):146-56. DOI: 10.1016/j.yexcr.2017.02.012. [ Links ]
36. Andia I, Maffulli N. New biotechnologies for musculoskeletal injuries. Surgeon. 2019;17(4):244-55. DOI: 10.1016/j.surge.2018.08.004. [ Links ]
37. Ornetti P, Nourissat G, Berenbaum F, Sellam J, Richette P, Chevalier X; under the aegis of the Osteoarthritis Section of the French Society for Rheumatology (Société Française de Rhumatologie, SFR). Does platelet-rich plasma have a role in the treatment of osteoarthritis? Joint Bone Spine. 2016;83(1):31-6. DOI: 10.1016/j.jbspin.2015.05.002. [ Links ]
38. Demange MK, Sisto M, Rodeo S. Future trends for unicompartmental arthritis of the knee: injectables & stem cells. Clin Sports Med. 2014;33(1):161-74. DOI: 10.1016/j.csm.2013.06.006. [ Links ]
39. Fernández-Cuadros ME, Perez-Moro OS, Miron-Canelo JA. Could Ozone be used as a feasible future treatment in osteoarthritis of the knee. Diversity Equal Health Care. 2016;13(3):232-9. [ Links ]
40. Fernandez-Cuadros M, Pérez-Moro O, Albaladejo-Florin M, Álava-Rabasa S. Symptomatic (Pain and Inflammation) and Disease-Modifying Effect(Minimal Joint Space) of Intra-articular Ozone (O2-O3)in Osteoarthritis of the Knee: a Clinical Case. SN Compr Clin Med. 2019;1:817-21. DOI: 10.1007/s42399-019-00122-0. [ Links ]
41. Fernandez-Cuadros ME, Perez-Moro OS, Albaladejo-Florin MJ, Algarra-Lopez R. Ozone Decreases Biomarkers of Inflammation (C-Reactive Protein and Erythrocyte Sedimentation Rate) and Improves Pain, Function and Quality of Life in Knee Osteoarthritis Patients: A Before-and-After Study and Review of the Literature. Middle East J Rehabil Health Stud. 2018;5(2):e64507. DOI: 10.5812/mejrh.64507. [ Links ]
42. Fernández-Cuadros ME, Pérez-Moro OS, Albaladejo-Florín MJ, Algarra-Lopez R. Intra Articular Ozone Reduces Serum Uric Acid and Improves Pain, Function and Quality of Life in Knee Osteoarthritis Patients: A Before-and-After Study. Middle East J Rehabil Health. 2018;5(3):e68599. DOI: 10.5812/mejrh.68599. [ Links ]
43. Fernández-Cuadros ME, Pérez-Moro OS, Albaladejo-Florín MJ. Knee osteoarthritis: Condroprotector action and symptomatic effect of ozone on pain, function, quality of life, minimal joint space and knee arthroplasty delay. Middle East J Rehabil Health. 2017;4(1):e43200. DOI: 10.17795/mejrh-43200. [ Links ]
44. Vannabouathong C, Bhandari M, Bedi A, Khanna V, Yung P, Shetty V, et al. Nonoperative Treatments for Knee Osteoarthritis: An Evaluation of Treatment Characteristics and the Intra-Articular Placebo Effect: A Systematic Review. JBJS Rev. 2018;6(7):e5. DOI: 10.2106/JBJS.RVW.17.00167. [ Links ]
45. Arias-Vázquez PI, Tovilla-Zárate CA, Bermudez-Ocaña DY, Legorreta-Ramírez BG, López-Narváez ML. Eficacia de las infiltraciones con ozono en el tratamiento de la osteoartritis de rodilla vs. otros tratamientos intervencionistas: revisión sistemática de ensayos clínicos. Rehabilitación. 2019;53(1):43-55. DOI: 10.1016/j.rh.2018.11.001. [ Links ]
46. Noori-Zadeh A, Bakhtiyari S, Khooz R, Haghani K, Darabi S. Intra-articular ozone therapy efficiently attenuates pain in knee osteoarthritic subjects: A systematic review and meta-analysis. Complement Ther Med. 2019;42:240-7. DOI: 10.1016/j.ctim.2018.11.023. [ Links ]
47. Zamboni F, Vieira S, Reis R, Oliveira M, Collins M. The potential of Hyaluronic Acid in immunoprotection and immunomodulation: chemistry, processing and function. Progr Mat Sci. 2018; 97:97-122. DOI: 10.1016/j.pmatsci.2018.04.003. [ Links ]
48. Chen WH, Lo WC, Hsu WC, Wei HJ, Liu HY, Lee CH, et al. Synergistic anabolic actions of hyaluronic acid and platelet-rich plasma on cartilage regeneration in osteoarthritis therapy. Biomaterials. 2014;35(36):9599-607. DOI: 10.1016/j.biomaterials.2014.07.058. [ Links ]
49. Iio K, Furukawa KI, Tsuda E, Yamamoto Y, Maeda S, Naraoka T, et al. Hyaluronic acid induces the release of growth factors from platelet-rich plasma. Asia Pac J Sports Med Arthrosc Rehabil Technol. 2016;4:27-32. DOI: 10.1016/j.asmart.2016.01.001. [ Links ]
50. Chevalier X, Sheehan B, Whittington C, Pourrahmat MM, Duarte L, Ngai W, et al. Efficacy and Safety of Hylan G-F 20 Versus Intra-Articular Corticosteroids in People with Knee Osteoarthritis: A Systematic Review and Network Meta-Analysis. Clin Med Insights Arthritis Musculoskelet Disord. 2020;13:1179544120967370. DOI: 10.1177/1179544120967370. [ Links ]
51. Tan J, Chen H, Zhao L, Huang W. Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Knee Osteoarthritis: A Meta-analysis of 26 Randomized Controlled Trials. Arthroscopy. 2021;37(1):309-25. DOI: 10.1016/j.arthro.2020.07.011. [ Links ]
52. Han SB, Seo IW, Shin YS. Intra-Articular Injections of Hyaluronic Acid or Steroids Associated With Better Outcomes Than Platelet-Rich Plasma, Adipose Mesenchymal Stromal Cells, or Placebo in Knee Osteoarthritis: A Network Meta-analysis. Arthroscopy. 2021;37(1):292-306. DOI: 10.1016/j.arthro.2020.03.041 [ Links ]
Received: February 20, 2021; Accepted: December 03, 2021