Arthritis and Bone Loss: A Hen and Egg Story
Purpose of review In this review, we will discuss the relation between bone loss and inflammation in rheumatoid arthritis.
Recent findings We highlight recent discoveries on the pathomechanisms of bone loss in rheumatoid arthritis and challenge traditional concepts by suggesting that bone loss may precede inflammation.
Summary During the clinical course of rheumatoid arthritis, inflammation is the key trigger for progressive local and systemic bone damage. Inflammatory cytokines induce the expression of molecules supporting the differentiation of osteoclasts, which are the primary bone-resorbing cells. However, bone loss can be observed in patients with recent-onset rheumatoid arthritis, suggesting that the start of the destructive phase of disease may be much earlier than previously expected. Recent data suggest that bone loss already starts during the autoimmune phase of the disease long before inflammation starts. Antibodies against citrullinated proteins thereby seem to be an important trigger for bone loss in the preclinical disease phase of rheumatoid arthritis. Although traditional concepts preferred a 'hen-egg' concept with inflammation coming first, later triggering bone loss, new data suggest an alternative 'egg-hen' concept, where bone loss arises before the clinical disease onset and may be important for priming of the joint for susceptibility to chronic inflammation.
Chronic inflammation is a typical condition initiating systemic bone loss. In particular, rheumatoid arthritis (RA) represents the prototype of a chronic inflammatory disease accompanied by rapid bone loss. Skeletal changes in patients with RA comprise local bone erosions, periarticular bone loss and systemic osteoporosis. Local bone erosion affects the juxta-articular cortical bone, which is in direct contact with the synovial inflammatory tissue. These lesions are characterized by destruction of the cortical bone lining, which leads to progressive destruction of the joint architecture and functional disability in the affected joint. Periarticular bone loss is characterized by the resorption of the trabecular bone close to inflamed joints, which yields the typical picture of periarticular osteoporosis. Finally, systemic bone loss results in premature osteoporosis of RA patients associated with increased fracture risk at both axial and appendicular skeletal sites.
Bone resorption and formation are constantly active throughout life. Two cell types are mainly responsible for this process, which is tightly regulated and balanced in healthy conditions: the bone-forming osteoblasts, from mesenchymal origin, and the bone-resorbing osteoclasts, large multinucleated cells from hematopoietic derivation. Bone loss results from an imbalance between osteoclasts and osteoblasts. Osteoclasts are subject to fine regulation by growth factor and cytokines, which permit the immune system to influence bone. Particularly during inflammation, the expression of essential growth factors for osteoclast differentiation, such as macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor kappa B ligand (RANKL), is induced.
Inflammation and bone loss are closely tied to each other in patients with RA. This interaction between inflammation and bone loss clinically reflects the molecular and cellular interactions between the immune system and the bone, also known as osteoimmunology. Considering that inflammation in patients with RA is long-standing and not self-limited, RA represents a model disease, which allows following the consequences of inflammation to the bone. Furthermore, there is a strong autoimmune feature of RA reflected by the formation of autoantibodies, which precedes the onset of inflammation in RA. Autoantibodies reflect the autoimmune state of RA and could also represent a factor which influences bone loss. Whereas traditional concepts suggest that bone destruction is the exclusive consequence of inflammation, recent data suggest that bone changes may precede the onset of inflammation in patients with RA.
Abstract and Introduction
Abstract
Purpose of review In this review, we will discuss the relation between bone loss and inflammation in rheumatoid arthritis.
Recent findings We highlight recent discoveries on the pathomechanisms of bone loss in rheumatoid arthritis and challenge traditional concepts by suggesting that bone loss may precede inflammation.
Summary During the clinical course of rheumatoid arthritis, inflammation is the key trigger for progressive local and systemic bone damage. Inflammatory cytokines induce the expression of molecules supporting the differentiation of osteoclasts, which are the primary bone-resorbing cells. However, bone loss can be observed in patients with recent-onset rheumatoid arthritis, suggesting that the start of the destructive phase of disease may be much earlier than previously expected. Recent data suggest that bone loss already starts during the autoimmune phase of the disease long before inflammation starts. Antibodies against citrullinated proteins thereby seem to be an important trigger for bone loss in the preclinical disease phase of rheumatoid arthritis. Although traditional concepts preferred a 'hen-egg' concept with inflammation coming first, later triggering bone loss, new data suggest an alternative 'egg-hen' concept, where bone loss arises before the clinical disease onset and may be important for priming of the joint for susceptibility to chronic inflammation.
Introduction
Chronic inflammation is a typical condition initiating systemic bone loss. In particular, rheumatoid arthritis (RA) represents the prototype of a chronic inflammatory disease accompanied by rapid bone loss. Skeletal changes in patients with RA comprise local bone erosions, periarticular bone loss and systemic osteoporosis. Local bone erosion affects the juxta-articular cortical bone, which is in direct contact with the synovial inflammatory tissue. These lesions are characterized by destruction of the cortical bone lining, which leads to progressive destruction of the joint architecture and functional disability in the affected joint. Periarticular bone loss is characterized by the resorption of the trabecular bone close to inflamed joints, which yields the typical picture of periarticular osteoporosis. Finally, systemic bone loss results in premature osteoporosis of RA patients associated with increased fracture risk at both axial and appendicular skeletal sites.
Bone resorption and formation are constantly active throughout life. Two cell types are mainly responsible for this process, which is tightly regulated and balanced in healthy conditions: the bone-forming osteoblasts, from mesenchymal origin, and the bone-resorbing osteoclasts, large multinucleated cells from hematopoietic derivation. Bone loss results from an imbalance between osteoclasts and osteoblasts. Osteoclasts are subject to fine regulation by growth factor and cytokines, which permit the immune system to influence bone. Particularly during inflammation, the expression of essential growth factors for osteoclast differentiation, such as macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor kappa B ligand (RANKL), is induced.
Inflammation and bone loss are closely tied to each other in patients with RA. This interaction between inflammation and bone loss clinically reflects the molecular and cellular interactions between the immune system and the bone, also known as osteoimmunology. Considering that inflammation in patients with RA is long-standing and not self-limited, RA represents a model disease, which allows following the consequences of inflammation to the bone. Furthermore, there is a strong autoimmune feature of RA reflected by the formation of autoantibodies, which precedes the onset of inflammation in RA. Autoantibodies reflect the autoimmune state of RA and could also represent a factor which influences bone loss. Whereas traditional concepts suggest that bone destruction is the exclusive consequence of inflammation, recent data suggest that bone changes may precede the onset of inflammation in patients with RA.