ENDOTARGET publication: The Hepatokine RBP4 Links Metabolic Diseases to Articular Inflammation
Andrés Pazos-Pérez, María Piñeiro-Ramil, Eloi Franco-Trepat, Ana Alonso-Pérez, María Guillán-Fresco, Antía Crespo-Golmar, Miriam López-Fagúndez, Javier Conde Aranda, Susana Belen Bravo, Alberto Jorge-Mora and Rodolfo Gómez
2023, Antioxidants
Background and Objectives:
Retinol Binding Protein 4 (RBP4) is a plasmatic vitamin A transporter that has been associated with inflammation in metabolic disorders (e.g., insulin resistance, metabolic syndrome, fatty liver). Moreover, altered levels of RBP4 have been reported in patients with rheumatic diseases, including rheumatoid arthritis, osteoarthritis (OA) and ankylosing spondylitis. Additionally, it is known that rheumatic diseases are often accompanied by metabolic alterations. Thus, this study investigates the relationship of RBP4 with metabolic disease and its influence on articular inflammation.
Results:
RBP4 is present in the synovial fluid of crystalline arthritis (CA) patients
RBP4 levels in synovial fluids of crystalline arthritis (CA) patients were assessed. Here, it was demonstrated that RBP4 is present in overlapping concentration ranges as described in OA patients. More precisely, synovial fluid RBP4 concentrations in CA patients correlated positively with glucose levels and negatively with synovial leukocyte count, which is a well-known marker of inflammation. Elevated levels of RBP4 were specifically noted in hypertensive patients, suggesting a strong link between metabolic dysregulation and joint inflammation.
RBP4 activates the inflammatory response in various articular cell types
RBP4’s impact on chondrocytes (cartilage cells) and synoviocytes (synovial cells) was analysed in vitro, demonstrating that RBP4 induces the expression of inflammatory factors in a dose dependent manner. In another experiment, it was shown that RBP4 synergically upregulates the interleukin (IL)-1β-mediated upregulation of several inflammatory genes. Further, it was shown that RBP4 promotes neutrophils activation in synoviocytes.
Toll-like receptor 4 (TRL4) is involved in the inflammatory response of RBP4
In silico molecular docking experiments suggest that RBP4 can directly dock to the TRL4 receptor, which is a key activator of the innate immune response and has a key role in the development of several rheumatic diseases. Experiments with chondrocytes indeed demonstrate that RBP4 acts most likely through TRL4.
RBP4 induces proteomic changes in chondrocytes
Proteomic analyses revealed that RBP4 triggers proteomic changes in vitro in chondrocytes consistent with inflammation. More precisely, RBP4 increased catabolism and decreased anabolism, mitochondrial dysfunction, and glycolysis promotion.
Conclusion:
The results of this study strengthen the hypothesis that RBP4 is a damaging associated molecular pattern (DAMP), thus related to inflammation and articular tissue destruction, as well as metabolic disruptions, suggesting a broader role in metabolic syndromes and their effects on joint health.
Read the full publication: The Hepatokine RBP4 Links Metabolic Diseases to Articular Inflammation
Glossary:
- Chondrocyte: cartilage cells that synthesise and maintain the cartilaginous matrix in cartilage tissue and are thus crucial for its structure and function.
- Crystalline Arthritis (CA): refers to a group of joint disorders, such as gout and pseudogout, characterised by the deposition of crystals in the joints, leading to inflammation and painful arthritis.
- Damaging Associated Molecular Pattern (DAMP): refers to molecules released by stressed or damaged cells that trigger an inflammatory response by the immune system.
- Interleukin-1 beta (IL-1β): pro-inflammatory cytokine protein produced by activated immune cells (macrophages) and involved in various cellular activities, including inflammation and immune responses.
- Osteoarthritis (OA): degenerative joint disease characterised by the breakdown of cartilage, leading to pain, swelling, stiffness, and reduced mobility in affected joints.
- Retinol Binding Protein 4 (RBP4): plasmatic vitamin A transporter that has been associated with inflammation in metabolic disorders.
- Synovial Fluid: viscous fluid within the cavities of synovial joints.
- Synoviocytes: specialised cells that line the inner layer of the synovial membrane in joints, responsible for producing synovial fluid and maintaining the health of joint tissues.
- Toll-like receptor 4 (TRL4): is a protein on the surface of immune cells that recognises specific bacterial molecules and triggers an immune response to defend against infections.