Abstract
Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in develo** OA therapeutic strategies.
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Introduction
Osteoarthritis (OA) is one of the most common types of arthritis and a chronic degenerative and disabling disease characterized by complex disorders of the whole synovial joint,1 including structural defects of hyaline articular cartilage, loss of intact subchondral bone, tissue hypertrophy and increasing of vascularity in the synovium, and instability of the tendons and ligaments (Fig. 1). In 2021, >22% of adults older than 40 had knee OA, and it is estimated that over 500 million individuals are currently affected by OA worldwide.2 Lacking long-term clinical treatment, OA patients at the end-stage of the disease are ultimately subjected to joint replacement surgery. Joint replacement surgery is growing at a rate of 10% per year globally, and 95% is performed for OA patients.3 However, the lifespan of the artificial joint is limited, and the risk of poor outcomes exists. By 2020, OA is globally estimated to be the fourth leading cause of disability, with a huge amount of medical and healthcare costs and indirect costs caused by loss of jobs and early retirement.
Phenotypes of Osteoarthritis (OA). Clinic evidence shows that the majority of OA patients have a diversity of OA phenotypes, including articular cartilage erosion, synovial hyperplasia, abnormal angiogenesis, synovial inflammation, subchondral bone disturbance, ligaments and tendons instability, and joint stiffness. Left-half side shows the structure of the normal synovial joint. Right-half side showed the possible alterations of synovial joint structure and symptoms in osteoarthritis
There is currently no cure for OA. It has been a long time since clinical treatments of OA focused on improving joint pain symptoms rather than on the decline of the disease progression. In recent years, strategies for OA have been shifted to its early prevention and halt or delay OA progression before massive destruction occurs. Therefore, understanding and identifying potential biomarkers and therapeutic targets at different stages of OA are urgent. Scientists and clinicians have devoted great efforts to defining major signaling pathways and molecules that play essential roles in the initiation and development of OA and could finally be developed as potential therapeutical targets to slow down or limit the damage to synovial joints.
Besides the updated epidemiology of OA, including its prevalence, incidence, burden, and risk factors, we have reviewed our current understanding of the pathogenesis in terms of synovial tissue interactions and cellular biology in OA, as well as pathological signaling pathways and essential molecules of OA. We have summarized the roles and functions of those pathological molecular signaling pathways and key molecules in different components of the synovial joints at different stages of OA and their related clinical relevance. We have finally reviewed current clinical therapies applied to OA patients and updated clinical trials of new drugs and biological treatments for future OA treatment.
Prevalence
Osteoarthritis (OA) is among the most prevalent diseases globally, which affects multiple joints, including the hip, knee, ankle, hand, and temporal-mandibular joint (TMJ) and other joints.1,4,5 The knee, hand, and hip joints are most susceptible to develo** OA.6 During the past century, the prevalence of OA has grown rapidly in part due to recent increases in lifespan and body weight.7,8 According to a large cohort study in the United States, the prevalence of knee OA has increased by 2.1-fold since the 1950s.9 It is anticipated that, by 2032, the prevalence of OA will rise from 26.6% to 29.5%.10 The prevalence rate of OA can be variable in different studies based on the definitions of OA, e.g., radiographic OA or symptomatic OA. In general, radiographic OA is more prevalent than symptomatic OA.11,43,44,45 In addition, aging-related mitochondrial dysfunction that induces oxidative stress, characterized by excessive accumulation of the reactive oxygen species (ROS) with the imbalance of energy metabolism of articular chondrocytes, is believed to promote articular chondrocyte apoptosis and articular cartilage destruction.46,47,48 Furthermore, age-related inflammation in the synovial joint, which is also associated with SASP, leads to destructive changes in the extracellular matrix (ECM) of the articular cartilage and promotes OA.49
Obesity is another major risk factor that leads to a higher incidence of hip and knee OA. Obesity is one of the most significant risk factors for knee OA partly because the excessive weight of obese patients leads to an abnormal increase in mechanical loading on knee joints, which results in the wearing and tearing of articular cartilage accompanied by ligament destruction and eventually leads to the occurrence of OA. Surprisingly, obese patients also have a higher incidence of OA in the hands that do not usually bear the weight.50,51 This leads to the general belief that it is the systemic factor(s) released by other tissues that induce OA in obese patients. In obese patients, cytokines released by adipocytes, also known as “adipokines”, such as resistin, visfatin, leptin, omentin, adiponectin, retinol-binding protein 4 (RBP4), and other factors, were reported to be associated with promoting the initiation and progression of OA.52,53,54,55,56 Furthermore, cytokines, such as TNF-α, IL-1, IL-6, and IL-8, were shown to trigger joint inflammation, which leads to ECM breakdown and cartilage degeneration.
OA affects more than 500 million populations worldwide, with a higher prevalence in the female gender than in males. Women are known to be more susceptible to OA onset and development than men are.6,57,58 Several studies showed that OA development could be triggered by the plunge in sex hormone levels in menopausal women.59,60 Besides, compared to male OA patients, female patients were reported to have higher levels of joint inflammation and clinical pain, thinner articular cartilage, and severe physical joint mobilities.57,60,61 The potential contributing factors for this gender difference in OA are not fully understood and need further attention in the OA research community.
Knee injury is another major risk factor for knee OA. Post-traumatic OA is one of the OA subtypes that occurs in those joints that have been injured. Current studies have shown that joints that have been traumatized are five times more likely to develop OA than joints that have never been damaged.62 U.S. clinical statistics predict that post-traumatic OA accounts for 12–42% of OA (the proportion varies by age), and the actual proportion could be higher.3 Trauma in the joints has been demonstrated to induce massive gene expression alterations in different compartments of knee joints. Besides injury, sports-related excessive joint loading also increases the chance of OA development. Professional athletes of high-impact sports present a higher prevalence of early knee OA than non-professional athletes and the universal population.63 The new technology of instrument innovations has been developed and utilized for investigating the role of joint mechanical stress in OA pathogenesis, which could study the pattern, force, and duration of mechanical stress on joint loading.64,65 Our advanced knowledge of how mechanical loading contributes to OA onset and progression is just beginning to be used in the applications of biomechanics assessment for guiding the clinical physical therapy of OA patients.66 However, the molecular mechanisms of how mechanical stress contributes to OA onset and development need to be investigated in great detail.
In comparison, few genetic mutations have been confirmed to be linked to human OA before. It is until recently that genetics has been discovered as a risk factor in 11 types of OA, including OAs in the hand, hip, and spine.67 A recently reported genome-wide association study (GWAS) meta-analysis of more than 820,000 East Asian and European individuals from 13 international cohorts of 9 populations, including over 170,000 OA patients, identified around 10,000 significantly associated single-nucleotide variants (SNVs), in which 100 were unique and showed independent genetic correlation with OA phenotypes and symptoms.67 Among these identified 100 SNVs, 60 were genome-wide significantly associated with more than one type of OA, and 77 potential effector genes were identified. Though genetic studies identified risk variants associated with new molecular signals and already reported effector genes contributing to the OA development,68,69,70,71 these genetic risk data need to be further verified and investigated to reveal options for the translational intervention of OA.
Clinical symptoms
Clinical symptoms of OA include joint functional limitations, stiffness, pain, disability of walking or running, and probably other symptoms.1,72,73 Bony enlargement and swollen and inflamed joints could be found in OA patients in physical examination. Clinical radiographic examination, such as MRI (magnetic resonance imaging), is able to visualize marginal osteophytes, joint space narrowing, structural changes of osteochondral tissue, and other OA lesions. Pain is one of the most distinctive symptoms and the main reason OA patients seek medical help,72 but the underlining mechanisms of OA pain are still poorly understood. Pain is a clinical indicator of tissue damage, inflammations, or disorders of the nervous system.74,75 Articular cartilage is an avascular tissue without any nerve invasion, and OA pain can happen both before and after an articular cartilage lesion detected by the imaging system. Therefore, it is unlikely that the destruction of articular cartilage directly causes OA pain. OA pain has been reported to be associated with synovitis and bone marrow lesion,76,77 as well as alterations in subchondral bone, osteophyte formation, abnormalities of infrapatellar fat pads, and lesion of ligaments, in which tissues have highly distributed sensory nerves.78 Molecular mechanisms underlying OA pain have been comprehensively updated and discussed in two recent review articles.79,80
Pathogenesis
During the past decades, the pathogenesis of OA has been extensively studied.81 Although its risk factors were characterized, and the structural changes of the synovial joint in OA are well understood, the complex pathological mechanisms of the onset and development of OA remain elusive. We summarize our current understanding of OA pathogenesis from the perspective of tissue interactions, changes in cellular biology, and pathogenic signaling pathways and molecules.
Tissue interactions in OA
Numerous studies reported that subchondral bone sclerosis could be one of the major reasons that cause aging-related OA and that the abnormal bone remodeling related to dysregulation of osteoblasts and osteoclasts plays key roles in the OA initiation and development.82,83,84,85,86,87 Increased subchondral bone porosity and remodeling, reduced bone density, and bone mineralization with irregular matrix organization, which were believed to be stimulated by bone-cartilage crosstalk through subchondral pores and vascular invasion, were observed in the early stage of OA.88,89,90,91 These changes in subchondral bone were found to be happening at the same time with or earlier than the early destruction of articular cartilage.92,93,94,95 On the other hand, the late stage of OA showed architectural alterations of the subchondral bone characterized by a reduction of bone remodeling and enhanced subchondral bone densification leading to sclerosis.96,97,98 However, the mechanism of how articular cartilage and joint issues crosstalk with subchondral bone leading to the initiation and development of OA is incompletely understood and needs further investigation.
Besides the subchondral bone dysregulation, the synovium is another most-related tissue that showed significant changes at the early stage of OA, even before cartilage degradation occurs.91,99 The contribution of synovium to the initiation and development of OA has been investigated in the past 20 years. At the early stage of OA, histological changes of the synovium include synovial lining hypertrophy and hyperplasia, increased angiogenesis, a low level of synovial inflammation, and synovial fibrosis observed.100,101,102,103 Synovitis with a high level of macrophages could be found at the end stage of the OA.104 Synovitis scores used as one of the OA assessments are based on these histological features.99,105,106 Low-grade synovial inflammation can be detected in >50% of OA patients at the early and late stages of the disease.107,108 Therefore, among the synovial features, synovial inflammation has received the most attention from the OA research community. It is widely believed that pro-inflammatory factors that are released by synovial tissue induce the ECM destruction of the articular cartilage. However, the interactions of different cell types in the synovial joint and features of the synovium at different stages of OA need to be extensively investigated.
Obesity acts as an OA risk factor not solely through loading excessive body weight onto knee joints,109 the pathogenesis involves a complex network of tissue and cellular interactions. As mentioned above, adipokines released by adipose tissue that interact with different tissues are believed to be critically involved in OA pathogenesis.110,111,342 Meanwhile, the signaling crosstalk between the BMP signaling pathway and the Wnt/β-catenin signaling pathway plays an important role in regulating cartilage homeostasis.343 Loss of TGFβR1 in mouse growth plate cartilage increased basal BMP activity, suggesting that TGFβR1inhibits BMP signaling in the development of the growth plate.344 However, the role of TGFβR1 and TGFβR2 in the homeostasis of articular cartilage is still unknown. How the non-canonical BMP pathway regulates the homeostasis of the articular cartilage and contributes to the OA onset and development remains to be determined.
The BMP signaling pathway is abnormal and unstable in OA patients.345 The expression of BMP-2 and BMP-4 in chondrocytes of articular cartilage of OA patients was significantly upregulated in the early stage and increased with OA degree. BMP-4 promoted the pathological remodeling of the osteochondral junction.346 OA significantly promoted BMP2 and MMP-13 expression in the subchondral bone of the experimental OA rat model. This increase was inhibited by intra-articular injection of noggin protein (a BMP2 inhibitor). Meanwhile, Noggin protein dramatically attenuated OA disease progression in early OA rat model.347 Moderate exercises increased the expression of BMP signaling pathway-associated proteins, such as BMP2, BMP6 and BMP receptor 2, and pSmad-5, thus inhibiting cartilage degeneration and attenuating the OA phenotype.348
More and more studies focus on the potential therapeutic targets of OA. miR-181a is critical for crosstalk between the BMP and Wnt/β-catenin signaling pathways and may become a target for OA therapy.349 BMP7-derived peptides ameliorated OA chondrocyte phenotype in vitro and attenuated cartilage degeneration in vivo.350 The clinical trial phase II of the intra-articular injection of BMP-7 for the treatment of knee OA patients was completed (NCT01111045) in 2011. BMP receptor type I (BMPRI) mimetic peptide CK2.1 promoted articular cartilage repair and inhibited chondrocyte hypertrophy through intra-articular injection.351 Several studies showed that BMP-2 and BMP-4 effectively decreased cartilage degeneration in combination with tissue engineering materials. Recombinant human BMP-2 promoted cartilage regeneration in injured cartilage in vitro and was evaluated in clinical trials (NCT00243295). Tissue engineering materials, such as porous Hydroxyapatite Collagen (HAp/Col), Conically GRADED scaffold of chitosan-hax Hydrogel/Poly (L-Lactide-co-Glycolide) (PLGA), and POLY caprolactone (PCL) scaffolds, combined with BMP-2 treatment greatly promoted cartilage regeneration and repaired the joint cartilage.352,353,354 BMP-3 inhibited cartilage regeneration in both partially and completely defective rabbit joint injury models by inducing ECM degradation, inhibited the expression of BMP-2 and BMP-4, and interfered with chondrocyte survival on the articular surface.355 The intra-articular injection of BMP-4 combined with muscle-derived stem cells (MDSCs) could efficiently repair articular cartilage damage in the experimental OA rat model.356 Regular intra-articular injections of BMP7 alleviated the damage to articular cartilage caused by strenuous running.357 The use of BMP6 combined with BMP2 or TGFB3 induced enhanced chondrogenesis of stem cells in vitro.358,359 The combined use of an osteogenic nanoparticulate mineralized glycosaminoglycan scaffold (MC-GAG) and BMP-9 promoted chondrogenic differentiation of primary human mesenchymal stem cells (hMSCs) by inducing increased expression of collagen II, aggrecan and cartilage oligomeric protein.360
FGF signaling pathways
The fibroblast growth factor (FGF) family is present in a wide range of animal species, including nematodes, zebrafish, mice, and humans.361 FGF signaling is involved in a variety of physiological processes, such as cell proliferation, migration, and differentiation.362 There are 18 FGFs in mammals, and they are FGFs1-10 and FGFs16-23. FGFs19, 21, and 23 are hormone-like FGFs that work in an endocrine fashion, and the other FGF members work in a paracrine fashion. FGFs ligands fulfill their functions through binding and activating FGF receptor (FGFR).362 The mammalian FGFR family consists of four members, FGFR1, FGFR2, FGFR3, and FGFR4. FGF signaling involves multiple downstream signaling pathways, including the RAS/MAPK, PI3K/AKT, and PLCγ pathways. In addition, FGF signaling can activate the STAT1/p21 pathway.363
FGF signaling plays a critical role in bone and cartilage development.363 FGFs/FGFRs function at various stages of bone and cartilage development from limb bud formation to long bone growth and maturation.363 FGFR1 and FGFR3 are the predominantly expressed FGF receptors in cartilage. FGFR2 expression is restricted to the pre-cartilage condensate zone, and FGFR2 can serve as an early marker of chondrocytes.364 During growth plate formation, FGFR1 is expressed in pre-hypertrophic and hypertrophic regions, and FGFR2 is observed in quiescent regions.365 FGFR3 was detected in the center of the mesenchymal condensation and all growth plate chondrocytes.364,365 At the same time, FGFs 1, 2, 5, 8, 9, 16–19, 21, and 23 are expressed in the growth plate chondrocytes, and FGFs 1, 2, 6, 7, 9, 18, 21, and 22 are expressed in the perichondrium.366
Previous studies have shown that FGFs 1, 2, 7, 8, 9,18, and 23 are the major ones associated with the pathogenesis of OA (Table 2), but they have diverse functions in the development of the joint disorder.367 The secretion and expression of FGF1 were significantly increased in the synovium in the late stages of the OA. FGF1 was reported to suppress ECM synthesis of the human articular chondrocytes and inhibit the expression of CCN2 (cellular communication network factor 2), which is an important factor that promotes the regeneration of damaged cartilage.368 FGF2 was reported to bind to perlecan, a heparan sulfate proteoglycan in the ECM, and functioned as a mechanosensor in articular cartilage.369 FGF2 binds to FGFR1 to upregulate the expression of MMP1 and MMP13 promoting matrix degradation through neuro-endocrine pathways in adult articular chondrocytes.370,371 FGF8 expression is upregulated in damaged synovium in a rabbit model of OA, and FGF8 was shown to enhance the production of proteases and prostaglandin E2 in inflamed synovial cells, thereby promoting cartilage degradation.372 The expression of FGF9 was downregulated in the human OA cartilage.373 Treatment of exogenous FGF9 attenuated cartilage degeneration but exacerbated the osteophyte formation in a mouse OA model.373 The function of FGF9 in articular cartilage remains to be defined. FGF18 was highly expressed in the superficial zone of articular cartilage and stimulated the expression and accumulation of type II collagen in articular chondrocytes to protect articular cartilage against degeneration.374,375,376 In addition, the FGF signaling pathway also plays an important role in synovitis. The synthesis and secretion of FGF1 were significantly increased in the synovial fibroblast in OA.377 FGFR2, which is one of the cognate receptors of FGF1, was upregulated in the synovial membrane in OA patients.377 FGF2 is a potent agent to promote the proliferation and chondrogenesis of synovial-derived stem cells.378 The expression of FGF8 was significantly upregulated in hyperplastic synovial cells and fibroblasts in the rabbit OA model.372 Deletion of FGFR1 in adult mouse articular chondrocytes inhibited the progression of articular cartilage degeneration, which was associated with MMP13 downregulation and FGFR3 upregulation.379 Zhou S et al. showed that deletion of FGFR3 in articular chondrocytes in mice resulted in OA-like defects in the temporomandibular joint, which were associated with upregulation of RUNX2 and Indian hedgehog (IHH).380 This suggests that targeting FGF may have a potential strategy for OA treatment. The clinical trials phase II of the only FGF-targeting drug for OA, recombinant human FGF18 (sprifermin), was finished in 2020 (NCT01919164). Intra-articular administration of 100 μg Sprifermin every 6 or 12 months significantly increased the thickness of the femorotibial joint cartilage after two years of treatment with no marked side effects.381
Runx2
Runt-related transcription factor 2 (Runx2) is a runt domain-containing transcription factor that binds to DNA as a monomer or, with higher affinity, as a part of a heterodimeric complex.430,431 Prg4 global knockout mice develop aging-related joint disorders with loss of chondrocytes in the superficial zone of articular cartilage and synovial cell hyperplasia.432 Running and fluid flow shear stress could promote the expression of Prg4 in the superficial zone chondrocytes in vivo and in vitro,433 suggesting the regulation of Prg4 expression can be partially controlled by mechanical forces. As a protective factor for joints, Prg4 is expressed by embryonic joint progenitors. Prg4 positive articular chondrocytes located on the surface of joint cartilage in adult mice have been demonstrated to be the progenitor for deeper layers of the mature articular cartilage.128,434 Exogenous recombinant human (rh) PRG4E was reported to promote ear wound closure and tissue regeneration by increasing VEGF expression and blood flow through a TLR (Toll-like receptor)-dependent mechanism in mice.435 Full-length recombinant human PRG4 (rhPRG4) produced by CHO-M cells and native human PRG4 (nhPRG4) purified from culture supernatants of human fibroblast-like synoviocytes from OA patients were also shown to bind to TLR2 and TLR4, mediating an anti-inflammatory factor.436 However, whether overexpressing Prg4 in the synovial joint can facilitate articular cartilage regeneration or prevent OA development remains to be determined. Lubricin was included as a potential biomarker in human synovial fluid in the diagnosis and progression of OA patients by a clinical observational study in 2022 (NCT02664870).
Other signaling factors
There are several other signaling cascades that have essential roles in the OA onset and development, such as notch signaling. Notch signaling was upregulated in mouse and human OA cartilage.437 Notch2 gain of function mutation in articular cartilage increased the severity of post-trauma OA by crosstalk with NF-κB, Wnt, and TGFβ signaling.438,439 Transient overexpression of NICD (NOTCH1 intracellular domain) led to enhanced synthesis of ECM and promoted the maintenance of articular cartilage, while constitutional overexpression of NICD resulted in early and progressive OA lesions in mice.437 Activation of Hes1, an essential mediator of Notch signaling, suppressed articular cartilage degradation and OA development by decreasing the Adamts5 and Mmp13 expression.440 The endoplasmic reticulum (ER) stress-triggered unfolded protein response (UPR) signaling has been identified as a contributing factor to OA pathology. Older OA patients developed ER stress in the early-stage OA when there was a higher synthesis of ECM proteins.441 How the UPR signaling mediated cell survival and the chronic ER stress-initiated apoptosis in cartilage and synovium contribute to the onset and development of OA needs to be investigated.
Clinical therapy and clinical trials
So far there is no effective cure for OA. The OA treatment approaches are divided into physical modalities, pharmacologic treatments, and surgical treatments.442 Several new therapies have also recently been developed. In the early stages of OA, treatment focuses on reducing pain and joint stiffness. Subsequently, treatment mainly focuses on maintaining joint physical function.443,444 In summary, OA treatment aims to reduce the disease symptoms and slow its progression.
Non-pharmacological treatment
Weight loss
Excessive body weight or obesity is a major risk factor for OA.445 Greater body weight adversely affects joint structure by adding additional load to the joints during daily activities and causing increases in the expression and production of enzymes that degrade the joints or increase joint inflammation.446 Weight loss is recommended for overweight or obese patients with low-extremity osteoarthritis.447
Exercise
According to the recommendations from the International Association for the Study of OA (OARSI), exercise is considered a core approach to the treatment of OA and is recommended for all patients.448 Exercise has been extensively studied as a treatment for OA.448 Uthman and colleagues found that exercise reduced painful movements and improved physical function in OA patients.449 The most common exercises used to treat OA include aquatic exercise,450 aerobic exercise,451 resistance exercise,451 multimodal exercise,452 and combination exercise.452,453
Assistive devices
OA patients often need assistive devices to compensate for decreased strength and impaired pain during exercise.454 Common devices include splints, braces, canes, functional shoes, and other training equipment.455 While there are some positive results from clinical studies, the need for assistive devices and their long-term safety remains in doubt.456
Physical therapy
Physiotherapy has significant therapeutic effects on OA, including therapeutic ultrasound, electrical stimulation, phototherapy, hydrotherapy, magnetotherapy, cryotherapy, and thermotherapy.457,458,459,460,461 Physical therapy provides significant relief of symptoms of OA, including pain, edema, and joint motion disturbances, and is suitable for emergency management in the acute phase.460 Instructing patients to use thermal agents has been recommended as a self-management strategy by the recent American College of Rheumatology Clinical Guidelines.462
Acupuncture
Acupuncture is a non-pharmacological treatment method in Chinese medicine.463,464 Acupuncture has analgesic and functional restorative effects in treating OA.463 The therapeutic effect of acupuncture may come from modulating inflammatory factors.463,465 However, there is evidence of uncertainty in the treatment of OA with acupuncture, particularly a significant difference between electro-acupuncture and hand acupuncture.466 In addition, non-pharmacological strategies, including health education, and lifestyle changes, such as diet, postural correction, and self-management, are important measures to prevent OA.467,468
Pharmacologic treatment
Currently, no drugs can alter the progression of OA and prevent long-term disability.469 Current international guidelines recommend medications for the treatment of OA that revolve solely around reducing the burden of the disease (symptomatic effects) and altering the natural course of the disease by slowing or stop** the biological process of tissue damage.469,470 The following classes of drugs are currently used to treat OA of the knee: non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, opioids, symptomatic, chondroprotective agents, and anti-cytokines.470,471,472
Paracetamol (acetaminophen) is the first-line analgesic for clinical pain control of arthritis.470 The safety profile of paracetamol relative to other analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs), has led to its increased use, resulting in paracetamol becoming one of the most common drugs used in OA treatment.470 However, there is evidence that paracetamol is associated with an increased risk of gastrointestinal, cardiovascular, and renal disease, as well as mortality.473 NSAIDs are commonly used anti-inflammatory and analgesic drugs in the treatment of OA.529
Artificial joint replacement
Arthroplasty is currently an effective clinical treatment for advanced knee OA. It effectively eliminates pain, corrects joint deformity, and improves knee function.530 However, clinical studies have found that some patients still do not recover satisfactorily after surgery and cannot fully straighten the knee.531 Cartilage injury, ligament injury, postoperative infection, and postoperative deep vein thrombosis in the lower extremity are all factors that influence the outcome of surgical treatment of knee OA, and early postoperative prevention of complications is crucial.531,532
Conclusions and perspectives
OA is a tremendously complex synovial whole-joint disorder, and how OA is initiated and developed remains poorly understood. Research on the cellular and molecular mechanisms of OA is still in the beginning phase. We have summarized from the current knowledge changes of key molecules in the essential signaling pathways in the articular cartilage, synovial membrane, subchondral bone, and synovial fluids of OA patients and animal models (Table 3), as well as the potential therapeutic reagents that have been reported (Table 4). Wnt, TNF, TGFβ/BMP, FGF pathway receptors, FA proteins, and other factors that are located on the chondrocyte membrane sense and transduce biochemical and mechanical signals. Activated signaling pathways and regulators, such as AMPK, mTOR, FGF, BMP, HIFs, and NF-κB, via crosstalk and feedback mechanisms in a complicated network, regulate the expression of key downstream factors, such as Runx2, MMP13, ADAMTS4/5, Prg4, and other factors, in articular chondrocytes and synovium. The initiation factors of OA are various, including excessive mechanical loading, inflammatory factors, aging and etc., which lead to the different primary effects of early-stage OA with unique molecular signaling signatures. The destruction and erosion of the articular cartilage, the synovial hyperplasia and inflammation, the abnormal angiogenesis of the synovial joint, the subchondral bone disturbance, and the instability of the ligaments and tendons could all contribute together or respectfully to the onset and progression of the disease. Scientists and clinic doctors are still debating, and there is still no conclusion on which one happens earlier than the others during the initiation of OA. No matter which pathological factor is the first dominant over others, or they contribute equally to the progression of OA; it has been well accepted that interference at the early stage of OA to prevent its progression will be a more efficient and effective strategy for better outcomes than focusing on the medical treatments and joint replacement surgery at the late and end-stage of the disease. Therefore, targeting critical signaling pathways and key molecules that are significantly changed at the early stage of the disease to control crosstalk between molecular pathways and the interaction of different compartments of synovial joint is critical for future research.
The multiple layers of complexity of the pathogenesis of OA and limited knowledge of the pathogenetic molecular signaling pathways and specific mechanisms have made the therapeutic pharmacological targeting of OA extremely difficult. At this point, in the future, a comprehensive understanding of alterations in distinct signaling pathways and expression of key factors in the superficial, middle and deep zones of articular cartilage and synovial membrane at different stages of OA triggered by different factors should be investigated in great detail. The whole picture of functions and regulations of each pathological signaling and key factors in various early-stage OA conditions could help us to develop more specific resolutions to halt or reverse the OA disease.
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Acknowledgements
We apologize to the authors whose relevant studies have not been included in this review article. This work was supported, in part, by the National Key Research and Development Program of China Grants (2019YFA0906004), the National Natural Science Foundation of China Grants (82230081, 82250710175, 82172375, 81991513, and 82261160395), the Shenzhen Stable Support Plan Program for Higher Education Institutions (20200925150409001), the Shenzhen Fundamental Research Program (JCYJ20220818100617036), the Shenzhen Key Laboratory of Cell Microenvironment Grant (ZDSYS20140509142721429) and the Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018).
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Q.Y. and G.X. conceptualized and wrote the outline of the manuscript. Q.Y., X.W., C.T., W.G., M.C., M.Q., Y.Z., T.H., and S.C. did the literature search and wrote the manuscript draft. G.X. reviewed and edited the manuscript. All authors have read and approved the final manuscript.
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Yao, Q., Wu, X., Tao, C. et al. Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Sig Transduct Target Ther 8, 56 (2023). https://doi.org/10.1038/s41392-023-01330-w
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DOI: https://doi.org/10.1038/s41392-023-01330-w
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