Targets, models and challenges in osteoarthritis research

Abstract

Osteoarthritis is a chronic degenerative disorder of the joint and represents one of the most common diseases worldwide. Its prevalence and severity are increasing owing to aging of the population, but treatment options remain largely limited to painkillers and anti-inflammatory drugs, which only provide symptomatic relief. In the late stages of the disease, surgical interventions are often necessary to partially restore joint function. Although the focus of osteoarthritis research has been originally on the articular cartilage, novel findings are now pointing to osteoarthritis as a disease of the whole joint, in which failure of different joint components can occur. In this Review, we summarize recent progress in the field, including data from novel 'omics' technologies and from a number of preclinical and clinical trials. We describe different in vitro and in vivo systems that can be used to study molecules, pathways and cells that are involved in osteoarthritis. We illustrate that a comprehensive and multisystem approach is necessary to understand the complexity and heterogeneity of the disease and to better guide the development of novel therapeutic strategies for osteoarthritis.

Keywords: Animal models; Bone; Cartilage; Osteoarthritis.

Fig. 1.

X-ray radiographic images showing structural alterations of the joints that are most commonly affected by OA. (A) Normal and (A′) severely affected joint of the hip, characterized by joint space narrowing (arrow) and osteophyte (bony outgrowth) formation (arrowheads). (B) Normal and (B′) severely affected joint of the knee, showing alterations in the medial compartment, with almost complete disappearance of the joint space (arrow) and lateral involvement. (C) Normal and (C′) severely affected joint of the hand. The panel shows the distal interphalangeal joint with disappearance of the joint space and small osteophyte formation (arrowheads).

Fig. 2.

Different steps in the discovery of two factors that play a key role in joint physiology and pathophysiology. Growth and differentiation factor-5 (GDF5) and frizzled-related protein (FRZB) were both originally identified from a chondrogenic extract of adult articular cartilage. In joint development, GDF5 is specifically expressed in the joint interzone, where the future joint will form. Mutations in the GDF5 gene result in severe skeletal malformations, with joint fusions in both mouse and human. In humans, single nucleotide polymorphisms (SNPs) within the GDF5 gene have been associated with OA susceptibility. In mouse mutants, more severe OA is observed. FRZB function is linked to chondrocyte proliferation during development. SNPs in the human FRZB gene have been associated with hip OA. Induced models of OA in mice show increased severity of disease in the absence of the Frzb gene.

Fig. 3.

Examples of in vivo mouse models of induced OA of the knee, with typical histological appearance and main features. Each panel shows a representative frontal hematoxylin–safranin-O-stained section of a mouse knee joint (medial condyle) with clear histopathological alterations: arrows indicate cartilage fibrillation, triangles indicate loss of proteoglycans and asterisks indicate loss of cartilage. (A) Intra-articular injections of collagenase are used to induce acute (within 1–3 weeks) damage to the ligaments and tendons of the knee. This will subsequently lead to secondary cartilage damage. (B) Intra-articular injection of papain leads to acute direct cartilage damage, mainly characterized by an obvious loss of proteoglycans. (C) Destabilization of the medial meniscus (DMM) is a more clinically relevant model in which dissection of the medial meniscus leads to destabilisation of the joint. After this surgical induction, mice develop mild to severe histological features of OA within 8 weeks. Scale bars: 200 μm; original magnifications 10×. AC, articular cartilage; BM, bone marrow; GP, growth plate; M, meniscus; S, synovium; SB, subchondral bone.