The spectrum of arthritis ranges from erosive (e.g., rheumatoid arthritis) to ossifying disease with formation of new bone (e.g., ankylosing spondylitis and osteoarthritis). The molecular basis for these different patterns of arthritis had long been unclear. In the last few years, however, characterisation of catabolic and anabolic molecular pathways in different forms of arthritis led to a better understanding of joint remodelling and revealed novel therapeutic targets.
Recent findings show that catabolic and anabolic molecular pathways govern bone and cartilage remodelling in healthy and arthritic joints. The predominance of catabolic molecular pathways (e.g., receptor activator of nuclear factor-κB ligand (RANKL)/RANK and cathepsin K) causes erosive disease whereas anabolic signalling (e.g., Wnt and fibroblast growth factor (FGF)18) favours the formation of new bone including bony spurs and subchondral sclerosis. Other pathways may have a dual function in arthritis (e.g., hedgehog) leading to either catabolic or anabolic joint remodelling dependent on other factors. Key mediators within these signalling pathways may serve as novel targets for treating pathological remodelling of bone and cartilage in arthritis.
Molecular pathways govern remodelling processes of bone and cartilage in arthritic joints. Future therapies will likely target the pathologic activity of these molecular pathways to specifically block either catabolic or anabolic joint remodelling in arthritis.
Joints face profound remodelling during the course of arthritis, affecting both articular cartilage and bone. The pathologic remodelling processes destroy physiological joint structure and impair joint function, leading to high morbidity in patients with arthritis. Joint remodelling can manifest as either progressive resorption (i.e., catabolic, erosive pattern) or paradoxical formation of new cartilage and bone (i.e., anabolic, osteophyte-like pattern). Whereas rheumatoid arthritis (RA) displays a catabolic phenotype with cartilage degradation and bone erosions, the anabolic patterns of joint remodelling in ankylosing spondylitis (AS) and osteoarthritis (OA) are marked by a spectrum of new-bone formation, ranging from subchondral sclerosis to bony spurs and joint fusion.
In healthy joints, degradation and formation of bone and cartilage are tightly controlled, which results in a steady state of bone and cartilage tissue. During arthritis, however, the articular homeostasis is severely disturbed; the balance between resorption and formation of bone and cartilage may shift to either of both sides, leading to catabolic or anabolic joint remodelling . In articular bone, osteoclasts and osteoblasts are the key cellular effectors of catabolic and anabolic processes , whereas chondrocytes preserve homeostasis in cartilage .
In arthritis with catabolic remodelling (e.g., RA) osteoclasts degrade bone and cause erosions. Osteoclasts originate from monocytes, which are attracted to the arthritic joint by inflammatory mediators. The differentiation of monocytes into osteoclasts necessitates the presence of receptor activator of nuclear factor-κB ligand (RANKL) among other factors. Of note, inflammatory cytokines such as tumour necrosis factor α (TNFα), interleukin (IL)-1, IL-6 and IL-17 can induce RANKL expression and osteoclast formation . Finally, bone degradation encompasses two major steps: osteoclasts secrete hydrochloric acid to demineralise bone and release matrix-degrading enzymes, including cathepsins, to digest the bone matrix . In anabolic forms of arthritis (e.g., OA and AS), osteoblasts, rather than osteoclasts, mediate remodelling processes. Osteoblasts derive from mesenchymal progenitors upon stimulation by parathyroid hormone, bone morphogenic proteins (BMPs) and Wnt proteins. Osteoblasts secrete bone-matrix proteins and promote mineralisation, with both processes leading to the formation of new bone.
Whereas mechanical stress is a major determinant of cartilage degradation in OA, pathological activation of catabolic cellular and molecular processes leads to the loss of cartilage in inflammatory types of arthritis. In RA, synovial fibroblasts and neutrophils within the synovial fluid, as well as chondrocytes, can release proteases that degrade cartilage. Interestingly, chondrocytes change their range of tasks from matrix production to release of matrix-degrading enzymes .
In the following, we explain the molecular basis for catabolic and anabolic joint remodelling in arthritis. We highlight interesting targets to re-establish tissue homeostasis of bone and cartilage in arthritic joints ( Fig. 1 ). Since some forms of arthritis show generalised involvement of the skeleton (i.e., osteoporosis) beyond local joint remodelling, we will finally address systemic effects of these novel therapeutic approaches.