Primary knee osteoarthritis (OA) remains an unmanageable degenerative disease. With increasing life expectancy and the obesity epidemic, OA is causing a growing economic and physical burden. Knee OA is a chronic musculoskeletal disease that may ultimately require surgical intervention. Therefore, patients continue to search for potential non-surgical treatments, such as injection of platelet-rich plasma (PRP) into the affected knee joint.
According to Jayaram et al., PRP is an emerging treatment for OA. However, clinical evidence of its effectiveness is still lacking, and its mechanism of action is uncertain. Although promising results have been reported regarding the use of PRP in knee OA, key questions such as conclusive evidence regarding its effectiveness, standard doses, and good preparation techniques remain unknown.
Knee OA is estimated to affect more than 10% of the global population, with a lifetime risk of 45%. Contemporary guidelines recommend both nonpharmacological (eg, exercise) and pharmacological treatments, such as oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, these treatments usually have only short-term benefits. Furthermore, drug use in patients with comorbidities is limited due to the risk of complications.
Intra-articular corticosteroids are usually only used for short-term pain relief because their benefit is limited to a few weeks, and repeated injections have been shown to be associated with increased cartilage loss. Some authors state that the use of hyaluronic acid (HA) is controversial. However, other authors reported pain relief after 3 to 5 weekly injections of HA for 5 to 13 weeks (sometimes up to 1 year).
When the above alternatives fail, total knee arthroplasty (TKA) is often recommended as an effective treatment. However, it is costly and may involve medical and postoperative adverse effects. Therefore, it is critical to identify alternative safe and effective treatments for knee OA.
Biological therapies, such as PRP, have recently been investigated for the treatment of knee OA. PRP is an autologous blood product with a high concentration of platelets. The effectiveness of PRP is thought to be related to the release of growth factors and other molecules, including platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, insulin-like growth factor type I (IGF-I), and vascular endothelial growth factor ( VEGF).
Several publications indicate that PRP may be promising for the treatment of knee OA. However, most disagree on the best method, and there are many limitations that limit proper analysis of their results, at risk of bias. The heterogeneity of the preparation and injection methods employed in the reported studies is a limitation in defining an ideal PRP system. Furthermore, most trials used HA as a comparator, which is controversial in itself. Some trials compared PRP to placebo and showed significantly better symptom improvement than saline at 6 and 12 months. However, these trials have considerable methodological flaws, including a lack of proper blinding, suggesting that their benefits may be overestimated.
The advantages of PRP for the treatment of knee OA are as follows: it is quite convenient to use due to its rapid preparation and minimal invasiveness; it is a relatively affordable technique due to the use of existing public health service structures and equipment; and it is likely to be safe , because it is an autologous product. Previous publications have reported only minor and temporary complications.
The purpose of this article is to review the current molecular mechanism of action of PRP and the extent of efficacy of intra-articular injection of PRP in patients with knee OA.
Molecular mechanism of action of platelet-rich plasma
The Cochrane Library and PubMed (MEDLINE) searches for PRI-related studies in knee OA were analysed. The search period is from the start of the search engine to December 15, 2021. Only studies of PRP in knee OA that the authors considered to be of greatest interest were included. PubMed found 454 articles, of which 80 were selected. An article was found in the Cochrane Library, which is also indexed, with a total of 80 references.
A study published in 2011 showed that the use of growth factors (members of the TGF-β superfamily, fibroblast growth factor family, IGF-I and PDGF) in the management of OA appears promising.
In 2014, Sandman et al. reported that PRP treatment of OA joint tissue resulted in a decrease in catabolism; however, PRP resulted in a significant decrease in matrix metalloproteinase 13, an increase in hyaluronan synthase 2 expression in synovial cells, and an increase in cartilage synthesis activity. The results of this study suggest that PRP stimulates the production of endogenous HA and reduces cartilage catabolism. PRP also inhibited the concentration of inflammatory mediators and their gene expression in synovial and chondrocytes.
In 2015, a controlled laboratory study showed that PRP significantly stimulated cell proliferation and surface protein secretion in human knee cartilage and synovial cells. These observations help to explain the biochemical mechanisms associated with the effectiveness of PRP in the treatment of knee OA.
In a murine OA model (controlled laboratory study) reported by Khatab et al. In 2018, multiple PRP releaser injections reduced pain and synovial thickness, possibly mediated by macrophage subtypes. Thus, these injections appear to reduce pain and synovial inflammation, and may inhibit OA development in patients with early-stage OA.
In 2018, a review of the PubMed database literature concluded that PRP treatment of OA appears to exert a modulating effect on the Wnt/β-catenin pathway, which may be important for achieving its beneficial clinical effects.
In 2019, Liu et al. investigated the molecular mechanism by which PRP-derived exosomes are involved in alleviating OA. It is important to highlight that exosomes play a crucial role in intercellular communication. In this study, primary rabbit chondrocytes were isolated and treated with interleukin (IL)-1β to establish an in vitro model of OA. Proliferation, migration, and apoptosis assays were measured and compared between PRP-derived exosomes and activated PRP to assess the therapeutic effect on OA. The mechanisms involved in the Wnt/β-catenin signaling pathway were investigated by western blot analysis. PRP-derived exosomes were found to have similar or better therapeutic effects on OA than activated PRP in vitro and in vivo.
In a mouse model of posttraumatic OA reported in 2020, Jayaram et al. suggest that the effects of PRP on OA progression and disease-induced hyperalgesia may be leukocyte-dependent. They also mentioned that leukocyte-poor PRP (LP-PRP) and a small amount of leukocyte-rich PRP (LR-PRP) prevent volume and surface loss.
The findings reported by Yang et al. The 2021 study showed that PRP at least partially attenuated IL-1β-induced chondrocyte apoptosis and inflammation by inhibiting hypoxia-inducible factor 2α.
In a rat model of OA using PRP, Sun et al. microRNA-337 and microRNA-375 were found to delay OA progression by affecting inflammation and apoptosis.
According to Sheean et al., the biological activities of PRP are multifaceted: platelet alpha granules promote the release of various growth factors, including VEGF and TGF-beta, and inflammation is regulated by inhibiting the nuclear factor-κB pathway
Concentrations of humoral factors in PRP prepared from both kits and the effects of humoral factors on macrophage phenotype were investigated. They found differences in cellular components and humoral factor concentrations between PRP purified using the two kits. The autologous protein solution LR-PRP kit has higher concentrations of M1 and M2 macrophage-related factors. Addition of PRP supernatant to the culture medium of monocyte-derived macrophages and M1 polarized macrophages showed that PRP inhibited M1 macrophage polarization and promoted M2 macrophage polarization.
In 2021, Szwedowski et al. Growth factors released in OA knee joints after PRP injection are described: tumor necrosis factor (TNF), IGF-1, TGF, VEGF, disaggregate, and metalloproteinases with thrombospondin motifs, interleukins, matrix metalloproteinases , epidermal growth factor, hepatocyte growth factor, fibroblast growth factor, keratinocyte growth factor and platelet factor 4 .
1. PDGF
PDGF was first discovered in platelets. It is a heat-resistant, acid-resistant, cationic polypeptide that is easily hydrolyzed by trypsin. It is one of the earliest growth factors that appear in fracture sites. It is highly expressed in traumatic bone tissue, which makes osteoblasts chemotactic and proliferates, increases the ability of collagen synthesis, and promotes the absorption of osteoclasts, thereby promoting bone formation. In addition, PDGF can also promote the proliferation and differentiation of fibroblasts and promote tissue remodeling.
2. TGF-B
TGF-B is a polypeptide composed of 2 chains, which acts on fibroblasts and pre-osteoblasts in a paracrine and/or autocrine form, stimulating the proliferation of osteoblasts and pre-osteoblasts and the synthesis of collagen fibers , as a chemokine, the osteoprogenitor cells are absorbed into the injured bone tissue, and the formation and absorption of osteoclasts are inhibited. TGF-B also regulates ECM (extracellular matrix) synthesis, has chemotactic effects on neutrophils and monocytes, and mediates local inflammatory responses.
3. VEGF
VEGF is a dimeric glycoprotein, which binds to receptors on the surface of vascular endothelial cells through autocrine or paracrine, promotes endothelial cell proliferation, induces the formation and establishment of new blood vessels, supplies oxygen to fracture ends, provides nutrients, and transports metabolic wastes. , providing a favorable microenvironment for metabolism in the local bone regeneration area. Then, under the action of VEGF, the alkaline phosphatase activity of osteoblast differentiation is enhanced, and local calcium salts are deposited to promote fracture healing. In addition, VEGF promotes the repair of soft tissue by improving the blood supply of the soft tissue around the fracture, and promotes the healing of fracture, and has a mutual promotion effect with PDGF.
4. EGF
EGF is a powerful cell division promoting factor that stimulates the division and proliferation of various types of tissue cells in the body, while promoting matrix synthesis and deposition, promoting fibrous tissue formation, and continuing to transform into bone to replace bone tissue formation. Another factor that EGF participates in fracture repair is that it can activate phospholipase A, thereby promoting the release of arachidonic acid from epithelial cells, and promoting the synthesis of prostaglandins by regulating the activities of cyclooxygenase and lipoxygenase. The role of resorption and later bone formation. It can be seen that EGF participates in the healing process of fractures and can accelerate fracture healing. In addition, EGF can promote the proliferation of epidermal cells and endothelial cells, and induce endothelial cells to migrate to the wound surface.
5. IGF
IGF-1 is a single-chain polypeptide that binds to receptors in bone and activates tyrosine protease after receptor autophosphorylation, which promotes the phosphorylation of insulin receptor substrates, thereby regulating cell growth, proliferation and metabolism. It can stimulate Osteoblasts and pre-osteoblasts, promote cartilage and bone matrix formation. In addition, it plays an important role in the coupling of bone remodeling by mediating the differentiation and formation of osteoblasts and osteoclasts and their functional activities. In addition, IGF is also one of the important factors in wound repair. It is a factor that promotes the entry of fibroblasts into the cell cycle and stimulates the differentiation and synthesis of fibroblasts.
PRP is an autologous concentrate of platelets and growth factors derived from centrifuged blood. There are two other types of platelet concentrates: platelet-rich fibrin and plasma-rich growth factor. PRP can only be obtained from liquid blood; it is not possible to obtain PRP from serum or clotted blood.
There are different commercial techniques to collect blood and obtain PRP. Differences between them include the amount of blood that needs to be drawn from the patient; isolation technique; centrifugation speed; amount to concentrate volume after centrifugation; processing time;
Different blood centrifugation techniques have been reported to affect the leukocyte ratio. Platelet numbers in 1 μL of blood from healthy individuals range from 150,000 to 300,000. Platelets are responsible for stopping bleeding.
The alpha granules of platelets contain different types of proteins such as growth factors (eg transforming growth factor beta, insulin-like growth factor, epidermal growth factor), chemokines, coagulants, anticoagulants, fibrinolytic proteins, adhesion proteins, Integral membrane proteins, immune mediators, angiogenic factors and inhibitors, and bactericidal proteins.
The exact mechanism of PRP action remains unknown. PRP appears to stimulate chondrocytes to remodel cartilage and the biosynthesis of collagen and proteoglycans. It has been used in various medical specialties such as oral and maxillofacial surgery (including temporomandibular OA), dermatology, ophthalmology, cardiothoracic surgery and plastic surgery.
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Post time: Jul-27-2022