Human Synovia Contains Trefoil Factor Family (TFF) Peptides 1–3 Although Synovial Membrane Only Produces TFF3: Implications in Osteoarthritis and Rheumatoid Arthritis

Abstract

Objective: Trefoil factor family peptide 3 (TFF3) has been shown to support catabolic functions in cases of osteoarthritis (OA). As in joint physiology and diseases such as OA, the synovial membrane (SM) of the joint capsule also plays a central role. We analyze the ability of SM to produce TFF compare healthy SM and its secretion product synovial fluid (SF) with SM and SF from patients suffering from OA or rheumatoid arthritis (RA). Methods: Real-time PCR and ELISA were used to measure the expression of TFFs in healthy SM and SM from patients suffering from OA or RA. For tissue localization, we investigated TFF1-3 in differently aged human SM of healthy donors by means of immunohistochemistry, real-time PCR and Western blot. Results: Only TFF3 but not TFF1 and -2 was expressed in SM from healthy donors as well as cases of OA or RA on protein and mRNA level. In contrast, all three TFFs were detected in all samples of SF on the protein level. No significant changes were observed for TFF1 at all. TFF2 was significantly upregulated in RA samples in comparison to OA samples. TFF3 protein was significantly downregulated in OA samples in comparison to healthy samples and cases of RA significantly upregulated compared to OA. In contrast, in SM TFF3 protein was not significantly regulated. Conclusion: The data demonstrate the production of TFF3 in SM. Unexpectedly, SF contains all three known TFF peptides. As neither articular cartilage nor SM produce TFF1 and TFF2, we speculate that these originate with high probability from blood serum.

Validation of the DNA Methylation Landscape of TFF1/TFF2 in Gastric Cancer

“…Trefoil factors (TFFs) are a group of stable polypeptides with a molecular weight of 6–12 kDa, which are secreted by mucus-secreting cells of the mammalian gastrointestinal epithelium. TFF1, TFF2, and TFF3 are essential components of the TFF family [ 20 , 21 , 22 , 23 ], which are expressed in the gastrointestinal tract and are present in virtually all mucous membrane [ 21 , 23 ]. Based on the special three-loop leaf-like structure, TFFs were extremely stable towards proteolytic digestion (including acid and heat degradation) [ 24 , 25 ].…”

“…Based on the special three-loop leaf-like structure, TFFs were extremely stable towards proteolytic digestion (including acid and heat degradation) [ 24 , 25 ]. Nowadays, TFF1 was confirmed to be necessary for the pathogenesis of breast cancer, and TFF2 was associated with the inflammatory bowel disease [ 22 , 23 , 26 ]. Although it has been shown that TFF1 and TFF2 are downregulated in primary gastric cancer [ 27 ], the interaction between TFFs and DNA methylation in gastric cancer remains unknown.…”

Trefoil Factor Family (TFF) Peptides and Their Links to Inflammation: A Re-evaluation and New Medical Perspectives

“…For the future, more sophisticated strategies can be expected, which could allow numerous novel medical applications for TFF peptides; possible fields would be inflammation-induced fibrosis, rheumatoid arthritis, or neurodegeneration. For example, TFF2 regulates airway remodeling [ 187 ], reversed airway fibrosis [ 108 ], and is upregulated in the synovial fluid of rheumatoid arthritis samples [ 188 ], whereas TFF3 is associated with neurodegeneration [ 189 ]. However, there are many open questions currently and there is a strong necessity for further research before application in clinics can be considered, e.g., for the treatment of various immune mediated inflammatory disorders.…”

Validation the DNA Methylation Landscape of TFF1/TFF2 in Gastric Cancer

“…Trefoil factors (TFFs) is a group of stable polypeptides with a molecular weight of 6-12 kDa, which is secreted by mucus-secreting cells of mammalian gastrointestinal epithelium. TFF1, TFF2, and TFF3 are essential components of the TFF family [20][21][22][23], which are expressed in the gastrointestinal tract and are present in virtually all mucous membrane [21,23]. Based on the special 3 loop leaf-like structure, TFFs were extremely stable towards proteolytic digestion (including acid and heat degradation) [24,25].…”

“…Nowadays, TFF1 was confirmed to be necessary in the pathogenesis of breast cancer, and TFF2 was associated with the inflammatory bowel disease [22,23,26]. Although it has been shown that TFF1 and TFF2 are downregulated in primary gastric cancer [27], the interaction between TFFs and DNA methylation in gastric cancer remains unknown.…”