Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

Dragan Primorac, Vilim Molnar, Eduard Rod, Željko Jeleč, Fabijan Čukelj, Vid Matišić, Trpimir Vrdoljak, Damir Hudetz, Hana Hajsok, Igor Borić, Dragan Primorac, Vilim Molnar, Eduard Rod, Željko Jeleč, Fabijan Čukelj, Vid Matišić, Trpimir Vrdoljak, Damir Hudetz, Hana Hajsok, Igor Borić

Abstract

Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee OA one of the leading causes of disability in elderly population. Today, we know that osteoarthritis is not a disease characterized by loss of cartilage due to mechanical loading only, but a condition that affects all of the tissues in the joint, causing detectable changes in tissue architecture, its metabolism and function. All of these changes are mediated by a complex and not yet fully researched interplay of proinflammatory and anti-inflammatory cytokines, chemokines, growth factors and adipokines, all of which can be measured in the serum, synovium and histological samples, potentially serving as biomarkers of disease stage and progression. Another key aspect of disease progression is the epigenome that regulates all the genetic expression through DNA methylation, histone modifications, and mRNA interference. A lot of work has been put into developing non-surgical treatment options to slow down the natural course of osteoarthritis to postpone, or maybe even replace extensive surgeries such as total knee arthroplasty. At the moment, biological treatments such as platelet-rich plasma, bone marrow mesenchymal stem cells and autologous microfragmented adipose tissue containing stromal vascular fraction are ordinarily used. Furthermore, the latter two mentioned cell-based treatment options seem to be the only methods so far that increase the quality of cartilage in osteoarthritis patients. Yet, in the future, gene therapy could potentially become an option for orthopedic patients. In the following review, we summarized all of the latest and most important research in basic sciences, pathogenesis, and non-operative treatment.

Keywords: cytokines; epigenomics; genetic therapy; knee osteoarthritis; mesenchymal stem cells; phenotype; platelet-rich plasma.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of cartilage extracellular matrix and its changes in osteoarthritis. (A) A healthy network of proteoglycan aggregates entangled with type II collagen fibres is seen. matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) cleavage sites are represented by red arrows; (B) Cartilage matrix changes in osteoarthritis defined by degradation of proteoglycans and cleavage of type II collagen fibres by ADAMTS and MMPs, respectively.
Figure 2
Figure 2
Microarchitectural and histologic changes of articular cartilage, subchondral bone and synovium in osteoarthritis. (A) Representation of normal joint structure and normal histologic state of the main tissue involved in osteoarthritis; (B) Early-stage osteoarthritis changes in articular cartilage, subchondral bone and synovium. Shallow cartilage erosions of the superficial tangential zone and middle transitional zone causing disruption of the extracellular matrix can be seen. Secondary chondrocyte hypertrophy and clustering is present as well. Changes to other joint tissues, mainly the reduction in subchondral bone mass, synovial thickening and inflammatory cells (lymphocytes) migration, together with changes in cellular activity and count, are depicted. (C) Late-stage osteoarthritis changes of involved tissues. Full-thickness cartilage erosions reaching the subchondral bone, chondrocyte apoptosis, subchondral bone sclerosis, osteophyte and subchondral cysts formation alongside vascular infiltration are shown. Further synovial thickening with immune cells infiltration and increased vascularization is also seen.

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