Bone Loss in Rheumatoid Arthritis: Basic Mechanisms and Clinical Implications

Abstract

Patients with rheumatoid arthritis (RA) have historically developed progressive damage of articular bone and cartilage, which correlates with disability over time. In addition, these patients are prone to periarticular and systemic bone loss, carrying additional morbidity. In contrast to what is seen in many other rheumatic diseases, the impact of inflammation on bone in RA is uniquely destructive. Loss of articular bone (erosions) and periarticular bone (demineralization) is a result of excessive bone resorption and markedly limited bone formation. There has been tremendous progress in preventing net bone loss in RA with the advent of disease-modifying agents, including biologic agents and small molecules, that both limit inflammation and may have a direct impact on the prevention of cytokine- and antibody-driven osteoclastogenesis. However, repair of existing bone erosions, although feasible, is observed infrequently. Lack of repair is a consequence of suppression of osteoblast function and bone formation by some of the same mechanisms that promote osteoclastogenesis and bone resorption. As new agents are introduced to control inflammation in RA, and novel mechanisms to target synovitis are identified, it may be possible in the future to fully repair damaged bone.

SEM BSE 3D Image Analysis of Human Incus Bone Affected by Cholesteatoma Ascribes to Osteoclasts the Bone Erosion and VpSEM dEDX Analysis Reveals New Bone Formation

“…Bone homeostasis is maintained balancing boneresorbing osteoclast and bone-forming osteoblast activity, alteration of this balance causes bone loss, that is not recov-ered by new bone formation. In fact, in inflammation, disease-like RA bone erosion results from excessive bone resorption and markedly limited bone formation [38]. We observed typical morphological markers of new bone formation on incus by CHO, but this phenomenon probably happens at a slower rate than bone resorption, so that bone loss is not compensed.…”

Activation of the Peroxisome Proliferator–Activated Receptor γ Coactivator 1β/NFATc1 Pathway in Circulating Osteoclast Precursors Associated With Bone Destruction in Rheumatoid Arthritis

“…Cytokines, such as tumor necrosis factor, interleukin‐1β (IL‐1β), IL‐6, and IL‐17, are effective triggers of bone resorption and some are now targeted in the clinic with inhibitors showing an effect on bone destruction . These cytokines induce osteoclast differentiation directly or indirectly by increasing the expression of RANKL, which leads to an increase in osteoclast differentiation and bone resorption activity, and subsequent bone erosion . Joint damage can be found in patients who have had RA for only a short time, and studies have shown enhanced levels of bone metabolism markers in RA patients with preclinical disease, which suggests that bone erosion might happen before the onset of clinical inflammation .…”

“…Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.40868/abstract. in osteoclast differentiation and bone resorption activity, and subsequent bone erosion (32)(33)(34). Joint damage can be found in patients who have had RA for only a short time, and studies have shown enhanced levels of bone metabolism markers in RA patients with preclinical disease, which suggests that bone erosion might happen before the onset of clinical inflammation (35,36).…”

PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients

“…Rheumatoid arthritis (RA) is an autoimmune disease, characterized by immune cell‐mediated destruction of the joints. Hyper‐reactive T and B lymphocytes are key cells in the destructive process by producing inflammatory cytokines and autoantibodies . The protein tyrosine phosphatase non‐receptor type 22 gene ( PTPN22 ) encodes the lymphoid protein tyrosine phosphatase LYP, which is expressed exclusively in hematopoietic cells, including T and B cells .…”

“…Hyper-reactive T and B lymphocytes are key cells in the destructive process by producing inflammatory cytokines and autoantibodies. 1 The protein tyrosine phosphatase non-receptor type 22 gene (PTPN22) encodes the lymphoid protein tyrosine phosphatase LYP, which is expressed exclusively in hematopoietic cells, including T and B cells. 2 LYP is a potent negative regulator of T and B lymphocyte activation by modulating T-cell receptor (TCR) and B-cell receptor (BCR) signaling.…”