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Lana, J.F.; Purita, J.; Everts, P.A.; De Mendonça Neto, P.A.T.; De Moraes Ferreira Jorge, D.; Mosaner, T.; Huber, S.C.; Azzini, G.O.M.; Da Fonseca, L.F.; Jeyaraman, M.; et al. Osteoarthritis Etiopathogenesis. Encyclopedia. Available online: (accessed on 11 December 2023).
Lana JF, Purita J, Everts PA, De Mendonça Neto PAT, De Moraes Ferreira Jorge D, Mosaner T, et al. Osteoarthritis Etiopathogenesis. Encyclopedia. Available at: Accessed December 11, 2023.
Lana, José Fábio, Joseph Purita, Peter Albert Everts, Palmerindo Antonio Tavares De Mendonça Neto, Daniel De Moraes Ferreira Jorge, Tomas Mosaner, Stephany Cares Huber, Gabriel Ohana Marques Azzini, Lucas Furtado Da Fonseca, Madhan Jeyaraman, et al. "Osteoarthritis Etiopathogenesis" Encyclopedia, (accessed December 11, 2023).
Lana, J.F., Purita, J., Everts, P.A., De Mendonça Neto, P.A.T., De Moraes Ferreira Jorge, D., Mosaner, T., Huber, S.C., Azzini, G.O.M., Da Fonseca, L.F., Jeyaraman, M., Dallo, I., & Santos, G.S.(2023, July 13). Osteoarthritis Etiopathogenesis. In Encyclopedia.
Lana, José Fábio, et al. "Osteoarthritis Etiopathogenesis." Encyclopedia. Web. 13 July, 2023.
Osteoarthritis Etiopathogenesis

Osteoarthritis (OA) is acknowledged as a major degenerative and progressive joint disease responsible for significant pain and disability in the adult population. The incidence of OA across the globe has risen significantly in the last few decades due to metabolic syndrome and aging. This disease can often be challenging to treat as it presents a multifactorial nature, being mainly characterized by the physiological and architectural changes in the joint compartment as a whole.

platelet-rich plasma platelet-rich fibrin hyaluronic acid

1. Introduction

Osteoarthritis (OA) is acknowledged as a major degenerative and progressive joint disease responsible for significant pain and disability in the adult population [1]. The incidence of OA across the globe has risen significantly in the last few decades due to metabolic syndrome and aging [2][3][4]. This disease can often be challenging to treat as it presents a multifactorial nature, being mainly characterized by the physiological and architectural changes in the joint compartment as a whole [5]. It is highly influenced by the interplay between innate and extraneous factors, consequently dictating disease progression and the patient’s response to treatments [6]. Based on the Kellgren–Lawrence scale (Table 1), the most common features of OA include progressive loss of articular cartilage, osteophyte formation, thickening of the subchondral bone, escalated synovial inflammation, ligament and meniscal degeneration, and overall joint hypertrophy [3]. The Kellgren–Lawrence scale is an important tool since it has been acknowledged as a valid and reliable radiographic grading system for OA and still remains one of the most widely used in clinical practice and in research [7][8][9].
Table 1. Osteoarthritis classification based on the Kellgren–Lawrence scale.
A variety of modalities have been used to treat osteoarthritis with both pharmacological and nonpharmacological alternatives to avoid surgical intervention [5]. Since OA symptoms are known to be intense, physicians may often prescribe patients a combination of drugs at different stages of the disease, aiming to block inflammatory nociceptive pain [10]. Nonsteroidal anti-inflammatory drugs (NSAIDs), other analgesics, and corticosteroids are commonly prescribed to aid in pain management. However, it is important to emphasize that prolonged administration of NSAIDs is a major health concern [11]. They do, in fact, promote temporary relief, but they can also make the patient more susceptible to the development of serious adverse events such as peptic ulcer disease, acute renal failure, and even myocardial infarction [11]. Nonpharmacological alternatives, on the other hand, are less aggressive in this sense but are still quite limited in terms of regenerative potential [12]. Physical therapy, low-impact exercise, weight loss, physical aids, and nerve ablation are typical examples of nonpharmacological strategies that may assist in the treatment of OA during its initial stages; however, these may not suffice in more severe and advanced stages, such as grade IV OA, where surgical intervention procedures may be inevitable [6][12].
These hurdles have motivated medical experts to develop novel alternative methods that are able to target the pathophysiological progression of OA without promoting secondary problems. Such alternatives are widely known as orthobiologics. However, due to the large number of differing reports in the literature, it is challenging to draw conclusive support regarding their use. In short, these biomaterials are derived from biological components that are naturally found in the body, with the ability to enhance the healing process of orthopedic conditions [13].
There are many popular examples given in the literature, such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), hyaluronic acid (HA), bone marrow aspirate/concentrate (BMA/BMAC), and even adipose tissue [14][15]. These products can have autologous or allogeneic origins and are known to be rich in cellular and molecular components [16]. For decades, these components have demonstrated a significant capacity to modulate not only the pathophysiology of OA but many other disease processes as well, providing great optimism in the field of regenerative medicine [16].

2. OA Etiopathogenesis

OA progression is driven by the by the intricate interplay of various local, systemic, and external factors, which consequently dictate the progression outcome and the patient’s response to treatment [6]. OA is characterized by multiple hallmarks, such as gradual degeneration of articular cartilage, the formation of osteophytes, thickening of the subchondral bone, increased inflammation of the synovium, deterioration of ligaments and menisci, and an overall increase in joint size [3].
The development of OA is the result of a combination of various factors, including genetic predisposition, obesity, traumatic injuries, aging, and the presence of other systemic diseases [17]. It affects the entire joint compartment, and previous research indicates that the degenerative process occurs in two distinct phases. Firstly, in the biosynthetic phase, chondrocytes attempt to repair the damaged extracellular matrix (ECM) repeatedly. Subsequently, in the degradative phase, elevated catabolic enzyme activity promotes digestion of the ECM and inhibits the synthesis of new ECM [10]. In healthy patients, a functional ECM contains a relative abundance of vital organic components, including water, chondroitin sulfate, type II collagen, proteoglycans, HA, and other proteins like fibronectin and laminin [18]. The fibrous components of the ECM are elastin and collagen, which consist of several types of fibrillar collagens such as types I, II, III, V, and XI, as well as nonfibrillar collagens including FACIT types IX, XII, and XIV, short chain types VIII and X, and basement membrane type IV [18]. When balanced, all of these components keep the ECM stabilized, preventing cellular damage.
Continuous biomechanical and biochemical stress causes secondary alterations, resulting in a predominant shift towards catabolic reactions. These biological processes disturb cellular activity, being therefore responsible for cartilage erosion and injury to the subchondral bone and peripheral structures, all of which worsen physical pain and debilitation [19]. The role of the innate immune system in OA has also been suggested by previous research [20]. This system is activated upon recognition of conserved motifs produced by pathogenic agents and/or cellular damage that occurs within tissues [21]. More specifically, this refers to damage-associated molecular patterns (DAMPs), which activate the innate immune system. DAMPs are generated as a result of damage to cellular and cartilage ECM products due to trauma, microtrauma, and even normal aging [22]. Usually, these molecular aggressors are fragments from proteoglycans, proteins, or residual cellular breakdown [23], which trigger a sterile inflammatory response upon interacting with particle recognition receptors (PRR), including toll-like receptors (TLR) on immune cell surfaces, or with cytosolic PRRs, such as nod-like receptors (NLRs) [21][22].
Furthermore, osteoarthritic synoviocytes and chondrocytes produce high levels of MMPs (matrix metalloproteinases) such as MMP-1, MMP-3, MMP-9, and MMP-13 [24]. Synoviocytes secrete proteolytic enzymes and proinflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α). These mediators play a role in both the progression of OA and the perception of painful stimuli associated with the condition [25]. Other molecules, such as resistin and osteopontin, are significantly elevated in osteoarthritic synovial tissue, and their increased expression is associated with disease severity [26][27][28]. Although cartilage itself produces most of the catabolic molecules via autocrine and paracrine signaling mechanisms, the synovium has also been reported to produce some chemokines and metalloproteinases that contribute to the degeneration of cartilage [29]. As a result, the breakdown products generated from cartilage degradation, either through biomechanical or biochemical insult, can stimulate the release of collagenase and other hydrolytic enzymes from synovial cells. This process contributes to vascular hyperplasia in the synovial membranes affected by OA [30].
In healthy individuals, articular cartilage is primarily composed of ECM that contains water, collagen, proteoglycans, and a small amount of calcium salt, as well as chondrocytes [31]. The turnover rate of collagen is relatively slow, while the turnover rate of proteoglycan is relatively faster [19]. Chondrocytes are responsible for controlling this process and are responsible for synthesizing molecular components, including proteolytic enzymes, which regulate the breakdown of the ECM in articular cartilage [19]. These cells are often exposed to various sources of noxious stimuli, including polypeptides, cytokines, biomechanical signals, and even fragmented components of the ECM itself [19]. Impaired homeostasis leads to an increase in water content and a decrease in proteoglycan content in the ECM. This results in a weakened collagen network due to decreased synthesis of collagen type II and increased breakdown of existing collagen. Additionally, there is an increase in the rate of chondrocyte apoptosis [32]. Ultimately, this paves the way for the onset of OA, which initiates when chondrocytes fail to maintain a balance between the synthesis and degradation of ECM components [33].
While macrophages can phagocytize microparticles and cellular debris, the overproduction of these particles can cause significant cell stress, making it harder to dispose of them. These accumulated particles then become mediators of inflammation themselves, stimulating chondrocytes to release more catabolic enzymes [34]. Collagen and proteoglycan breakdown products can also be processed by synovial macrophages, triggering the release of TNFα, IL-1, and IL-6. These molecules can bind to chondrocyte receptors, leading to the further release of MMPs and inhibition of the synthesis of collagen type II. This sequence of events can exacerbate cartilage degeneration and create a more debilitated microenvironment [35].


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