What is the most common autoimmune disorder? The correct answer is Rheumatoid Arthritis (RA), affecting more than 18 million people worldwide, with annual treatment costs estimated at $20,000 per patient. Nearly 70% of RA patients are women.
In our previous posts, we explored the intricate relationship between the immune system and bone health, and how immune dysregulation in autoimmunity leads to bone impairment and loss. Abnormal immune system activation, a hallmark of autoimmunity, negatively affects the skeletal system, reinforcing the significance of osteoimmune interactions within the field of osteoimmunology (6). In this post, we dive deeper into the consequences of immune dysfunction and its impact on bone health in Rheumatoid Arthritis (RA).
Rheumatoid Arthritis and Bone Health
RA is a chronic autoimmune disease characterized by immune dysregulation and persistent joint inflammation. It is a leading cause of inflammatory arthritis in adults, significantly impairing the structure and function of joints. A defining feature of RA is bone loss, driven by an imbalance between bone-resorbing osteoclasts and bone-forming osteoblasts. This results in erosive bone damage that lacks proper repair mechanisms. If left untreated, RA can lead to progressive bone erosion and functional disability of the joints.
Studies have identified RA as an independent risk factor for osteoporosis, increasing the likelihood of osteoporotic fractures (1,4,8). Compared to healthy individuals, RA patients face:

  • A twofold increased risk of developing osteoporosis.

  • Two-to-threefold higher risk of hip fractures.

  • Two-to-sixfold higher risk of vertebral fractures.

Osteoimmune Crosstalk in RA Pathogenesis
RA-related bone destruction is driven by complex interactions between immune cells, inflammatory mediators, and bone-regulating factors. Key mechanisms include:

  • Synovial inflammation in RA leads to destruction of bone and cartilage in joints (7).

  • Periarticular bone loss (osteopenia) occurs early, while systemic bone loss involves both the appendicular and axial skeleton. The accelerated loss of cortical and cancellous bone makes RA patients more prone to osteoporotic fractures (8).

  • Inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-17 contribute to osteoclast activation and simultaneously suppress osteogenesis (8).

  • T-helper 17 cells (Th17 cells, named for synthesis of IL-17) are abundant in the inflamed synovium and amplify the secretion of inflammatory cytokines. This, in turn, promotes local inflammation and osteoclast differentiation. Th17 also triggers RANKL expression, further promoting bone resorption (7,8).

  • Synovial fibroblasts, stimulated by IL-17, upregulate RANKL expression, fueling osteoclast activity. Circulating monocytes migrate to inflamed joints, where pro-inflammatory cytokines facilitate their transformation into osteoclasts (2,7-9).

  • B lymphocytes exacerbate bone loss by interacting with osteoclast Fcγ receptors and promoting osteoclastogenesis. Meanwhile, Tumor Necrosis Factor (TNF) suppresses osteoblast-driven bone formation via inhibition of Wnt signaling through dickkopf-related protein 1 (DKK1) and sclerostin, further restraining bone regeneration (7).

  • Autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) initiate early structural bone damage, even in the preclinical phase of RA. Inflammation accelerates this process by amplifying osteoclast formation and bone resorption, highlighting that RA progression begins long before clinical symptoms appear (3,5,8).

  • Joint synovium autoantibodies form immune complexes, activating complement pathways that intensify inflammation and tissue destruction. Chronic inflammation further induces angiogenesis, recruiting more inflammatory cells, and systemic cytokines may trigger extra-articular effects such as rheumatoid nodules and muscle protein degradation (6).

Advancing RA Treatment Strategies
Understanding the mechanism of pathogenesis in RA and the impact of autoantibodies and cytokines can inform the design of innovative therapeutic approaches to mitigate autoimmune-mediated bone loss. At Molecular Matrix, Inc., we are dedicated to pioneering novel therapeutics for bone diseases. A deeper comprehension of osteoimmune interactions will guide the development of more effective treatment or prevention strategies for RA.
References:

  1. Amarasekara, D. S., Yu, J., & Rho, J. (2015). Bone Loss Triggered by the Cytokine Network in Inflammatory Autoimmune Diseases. Journal of Immunology Research, 2015, 1–12. https://doi.org/10.1155/2015/832127

  2. El Khassawna, T., Serra, A., Bucher, C. H., Petersen, A., Schlundt, C., Könnecke, I., Malhan, D., Wendler, S., Schell, H., Volk, H.-D., Schmidt-Bleek, K., & Duda, G. N. (2017). T Lymphocytes Influence the Mineralization Process of Bone. Frontiers in Immunology, 8, 562. https://doi.org/10.3389/fimmu.2017.00562

  3. Ingegnoli, F., Castelli, R., & Gualtierotti, R. (2013). Rheumatoid Factors: Clinical Applications. Disease Markers, 35, 727–734. https://doi.org/10.1155/2013/726598

  4. Kamen, D. L., & Alele, J. D. (2010). Skeletal manifestations of systemic autoimmune diseases. Current Opinion in Endocrinology, Diabetes & Obesity, 17(6), 540–545. https://doi.org/10.1097/MED.0b013e328340533d

  5. Liu, J., Gao, J., Wu, Z., Mi, L., Li, N., Wang, Y., Peng, X., Xu, K., Wu, F., & Zhang, L. (2022). Anti-citrullinated Protein Antibody Generation, Pathogenesis, Clinical Application, and Prospects. Frontiers in Medicine, 8, 802934. https://doi.org/10.3389/fmed.2021.802934

  6. Lončar, S. R., Halcrow, S. E., & Swales, D. (2023). Osteoimmunology: The effect of autoimmunity on fracture healing and skeletal analysis. Forensic Science International: Synergy, 6, 100326. https://doi.org/10.1016/j.fsisyn.2023.100326

  7. Okamoto, K. (2024). Crosstalk between bone and the immune system. Journal of Bone and Mineral Metabolism, 42(4), 470–480. https://doi.org/10.1007/s00774-024-01539-x

  8. Schett, G. (2017). Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis. Modern Rheumatology, 27(2), 193–197. https://doi.org/10.1080/14397595.2016.1265907

  9. Umur, E., Bulut, S. B., Yiğit, P., Bayrak, E., Arkan, Y., Arslan, F., Baysoy, E., Kaleli-Can, G., & Ayan, B. (2024). Exploring the Role of Hormones and Cytokines in Osteoporosis Development. Biomedicines, 12(8), 1830. https://doi.org/10.3390/biomedicines12081830

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