The Research Progress on Sports Applications in Osteoarthritis

INTRODUCTION

Osteoarthritis is one of the most prevalent joint diseases which is characterized by a high disability rate and high morbidity rate, the number of osteoarthritis patients has been increasing rapidly in recent years, with estimates suggesting there are almost 8% of the global population in the world will suffer from osteoarthritis in the future; Furthermore, osteoarthritis is becoming the fourth leading cause of disability to affect employment and quality of life worldwide [1]. The main symptoms of osteoarthritis include joint pain, swelling, stiffness, and joint dysfunction; pain is the most prevalent symptom of osteoarthritis, often persisting for an extended period [2]; Typically, the initial clinical manifestation of osteoarthritis is significant pain at the onset of joint movement, with partial pain relief after slight movement, and aggravated pain due to excessive exercise and weight-bearing [3, 4]. Furthermore, osteoarthritis is also a kind of age-related chronic disease, statistical data demonstrated that the incidence rate of osteoarthritis increases with age, with a significantly higher prevalence observed in the elderly compared to younger individuals [5, 6].

Currently, there is no optimal treatment for osteoarthritis. As a kind of progressive chronic disease, osteoarthritis eventually experiences bone and joint replacement because of deterioration and inadequate treatment. The pathogenesis of osteoarthritis is complex, with numerous risk factors, including joint injury, joint overuse, age, and overweight, which have the potential to cause osteoarthritis [7, 8]; additionally, biomechanics, inflammation, and metabolic factors also play a role in the onset and progression of osteoarthritis, leading to damage to tissue structure [9, 10]. Engaging in sports has been demonstrated to facilitate metabolic processes, enhance blood circulation, reduce body weight and oxidative stress, augment muscle mass and muscle control ability, and prove more efficacious in managing osteoarthritis. The accumulative research data demonstrated that engaging in appropriate physical activities and maintaining a balanced diet can reinforce muscles and preserve a healthy weight, thereby mitigating the symptoms of osteoarthritis [11-13]. In order to gain further insight into the impact of sports on osteoarthritis and the underlying mechanism involved, this review introduced the pathogenesis and the risk factors associated with osteoarthritis, presented a summary of findings on the use of sports in the management of osteoarthritis, discussed the limitations of such applications, we hope that this review may provide a foundation for the development of more effective treatments for osteoarthritis.

The Pathogenesis of Osteoarthritis

Normally, the bone joint is connected by a capsule composed of connective tissue between adjacent bones, each joint includes the joint surface, joint capsule, joint cavity, and some joints also have auxiliary structures such as ligaments, joint discs, and meniscus. In the context of long-term weight-bearing or fatigue, the cartilage within a joint appears to undergo deterioration, and this results in the reactive proliferation of the attachment of the marginal ligaments and subchondral bone, which in turn leads to the formation of osteophytes and, ultimately, the development of arthritis [14]. One of the convinced pathological processes is the mechanical injury-induced inflammatory response, which further increases the expression of proteases, and results in the degradation of the extracellular matrix and cartilage degeneration [15, 16]. A substantial body of evidence has demonstrated that inflammatory factors, including interleukin-1, interleukin-17, tumor necrosis factor-α, and matrix metalloproteinase are intimately associated with osteoarthritis, the regulation of the expressions of inflammatory factors has been shown to markedly alleviate the symptoms of osteoarthritis [17-19]. For example, Libin Ni et al. demonstrated that itaconate, a kind of tricarboxylic acid cycle metabolite with anti-inflammatory effects, could alleviate the inflammation of osteoarthritis by activating Nrf2 and inhibiting the expression of NF-κB [20]; similarly, Bahareh Sadri et al. demonstrated that adipose-derived mesenchymal stromal cells (ADMSCs) could result in a decrease in the expression of IL-10 in patients with knee osteoarthritis after a three-month treatment [21]; furthermore, Manabu Kawata et al. indicated that Krüppel-like factor 4, a transcription factor associated with inflammation, participated in the mocetinostat treatment in osteoarthritis [22, 23]. Furthermore, nitric oxide, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), matrix metallopeptidase 13 (MMP13), interleukin-8 (IL-8), Chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-1b (IL-1b), and interleukin-2β (IL-2β) have been identified as key contributors to pathogenesis of osteoarthritis, and they have been reported to play an important role in the pathogenesis of osteoarthritis [24-27].

In addition to inflammatory factors, immune regulation may also play a significant role in the pathogenesis of osteoarthritis, the accumulating data demonstrated that osteoarthritis frequently occurs in conjunction with synovitis, a condition characterized by a low-grade innate immune system. This distinctive immunoregulatory disease could affect the progression of osteoarthritis [28, 29]. For example, Bizhi Tu et al. comprehensively analyzed the effect of arachidonic acid metabolism genes in osteoarthritis synovium by multiple gene analysis, found that there were several kinds of immune statuses in different clusters, reduced infiltration of immune cells was observed in the older patients with osteoarthritis, and macrophages and B cells expressed the higher levels of hub genes. These observations highlight the crucial role of synovial immune processes in osteoarthritis pathogenesis [30]; furthermore, Junchen Li et al. screened the osteoarthritis-related immune genes by WGCNA and AI technology, found that immune-related genes, including Frizzled-7 (FZD7), interleukin 1 receptor-associated kinase 3 (IRAK3), KDEL endoplasmic reticulum protein retention receptor 3 (KDELR3), polyhomeotic homolog 2 (PHC2), Ras homolog family member B (RHOB), ring finger protein 170 (RNF170), SRY-box transcription factor 13 (SOX13), and Zinc finger with KRAB and SCAN domains 4 (ZKSCAN4) were identified as having the high diagnostic value in osteoarthritis [31]. Aimy Sebastian et al. provided the evidences that multiple immune cell types, including monocytes, B cells, T cells, and dendritic cells were present in the osteoarthritis joints, and they observed a notable alteration in the number of monocytes and macrophages between the pre-and post-injury states [32].

Oxidative stress can be defined as a kind of physiological and pathological process with the production or accumulation of excessive oxidative molecules, that exceed the antioxidant capacity of cells or tissues, ultimately leading to oxidative damage to biomolecules [33]. There is a growing body of evidence to suggest that oxidative stress may be a contributing factor in the development of several kinds of diseases, including cancer, diabetes mellitus, cardiovascular disease, and atherosclerosis [34-37]. The evidences demonstrated that oxidative stress also may be involved in the pathogenesis of osteoarthritis. For example, Liang Liu et al. validated the effects of α-ketoglutarate on osteoarthritis, and found that α-ketoglutarate downregulated the expressions of MMP13, A disintegrin, and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), IL-6, and tumor necrosis factor-α (TNF-α) by regulating mitophagy and inhibiting the generation of ROS [38]; similarly, Zizheng Chen et al. provided the evidences that a specific circular RNA, circFNDC3B, may enhance the proliferation of chondrocytes and mitigate the degradation of the extracellular matrix by reducing the oxidative stress and regulating the NF-κB-mediated signaling pathway [39]; additionally, Bohao Chen et al. demonstrated that curcumin and catalase could inhibit the oxidative stress and alleviate the symptoms of knee osteoarthritis by upregulating the expression of antioxidant enzymes and reducing reactive oxygen species [40].

The evidences demonstrated that the number and the activity of chondrocytes were decreased in osteoarthritis, with the apoptosis rates of chondrocytes reaching 20% of the total number of chondrocytes in osteoarthritis joints, indicating that apoptosis of chondrocytes may play a direct role in the pathogenesis of osteoarthritis directly [41-43]. Hongjun Zhang et al. demonstrated that miR-146a-5p could be significantly upregulated in knee cartilage tissue, leading to an increase in the apoptosis of chondrocytes in osteoarthritis patients, they also showed that miR-146a-5p antagomir could alleviate the effect of miR-146a-5p on osteoarthritis [44]; Yuan Liu et al. conducted a comparative analysis of normal individuals and osteoarthritis patients, found that there was the presence of chondrocyte apoptosis in osteoarthritis patients and a reduced expression of α7 nicotinic acetylcholine receptors (α7-nAChRs) in osteoarthritis patients, and the administration of nicotine was observed to mitigate chondrocyte apoptosis by regulating α7-nAChRs [45]; J E Dilley et al. found that the expression of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was increased by regulating matrix metalloproteinase 13 (MMP-13), and the inhibition of the CAMKK2 expression could decrease the chondrocyte apoptosis in osteoarthritis patients [46].

The Sports Applications in Osteoarthritis

Pain is the primary symptom of osteoarthritis; manifesting intermittently or continuously; a multitude of inflammatory factors accumulate around the joints and within chondrocytes to result in the severity of osteoarthritis. The osteoarthritis-induced immune response and oxidative stress stimulate peripheral sensitivity of the nervous system and central nervous system, thereby resulting in pain. Sports are various conscious activities that gradually develop in the process of human development as a means of fostering physical fitness, they have been shown to play a role in weight management, disease prevention, emotional well-being, and vitality [47, 48]; Additionally, sports may facilitate accelerated energy metabolism, regulate multiple kinds of signaling pathways, and influence gut microbiota within the human body, thereby reducing the inflammatory responses, and alleviating the symptoms of osteoarthritis. For example, Jiabao Liu, confirmed that moderate treadmill exercise could decrease the expressions of IL-1β and MMP13, thereby slowing the process of chondrocyte pyroptosis in osteoarthritis by regulating PI3K/Akt/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways [49]; similarly, Liang Chen et al. demonstrated that treadmill and wheel exercise could significantly decrease the expressions of IL-1β, IL-6, and TNF-α, improve the Mankin’s score and knee diameter in osteoarthritis rats by regulating the JNK/NF-κB signaling pathways [50]; furthermore, Kefeng Li et al. proved that moderate exercise could alleviate the inflammatory response, decrease the expressions of TLR4 and MMP-13, and increase the gut microbial diversity in osteoarthritis mice [51], Furthermore, Xiaoxia Hao et al. observed the effect of treadmill-walking on post-traumatic osteoarthritis rats. The results demonstrated that treadmill-walking resulted in a reduction in the abundance of the phylum TM7 and an increase in the abundance of the phylum Fusobacteria; the genus Lactobacillus and the genus Adlercreutzia were observed to affect the structural osteoarthritis phenotypes, and the phylum Fusobacteria and the genus Cetobacterium were found to be significantly associated with the effects of exercise [52]. A summary of the recent progress on the effect of sports on osteoarthritis by regulating the inflammatory response is presented in Table 1.

Abbreviations: TNF-α, tumour necrosis factor α; IL-1β, interleukin-1β; IL-6, interleukin-6; MCP1, monocyte chemoattractant protein-1; MMP3, matrix metalloproteinase 3; MMP-13, matrix metalloproteinase 13; IFN-γ, Interferon-γ; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; TLR4, Toll-like receptor 4; iNOS, inducible nitric oxide sythase; HDAC3, Histonedeacetylase 3; ADAMTS-5, Recombinant A disintegrin and metalloproteinase with thrombospondin 5; NO, nitric oxide; MDA, malondialdehyde; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor kappa-B; PI3k-Akt, Phosphoinositide 3-kinase-Akt; P2X7, Purinergic 2X7 receptor; AMPK, Adenosine 5‘-monophosphate (AMP)-activated protein kinase; mTOR, Mammalian target of rapamycin; PGC-1α, Peroxisome proliferators-activated receptor γ coactivator l alpha.