There is a single protein that also has potential as a biomarker for RA, with the unusual name of 14-3-3η. The name refers to chromatography and electrophoresis patterns: elution in the 14th fraction of bovine brain homogenate in DEAE-cellulose chromatography, and location in positions 3.3 of subsequent starch-gel electrophoresis. 14-3-3 is a family of seven intracellular “chaperone” proteins, which fold and move proteins within the cell. The structure includes nine α helices with variable amino and carboxyl termini. The N-terminus forms a cuplike “amphipathic” groove (can bind both hydrophilic and lipophilic structures), which interacts with more than 200 intracellular proteins, representing a wide array of biologic processes: protein synthesis, cellular metabolism, protein trafficking, signal transduction, cytoskeletal transport, apoptosis and transcription.
Further, at the extracellular level, 14-3-3 is a ligand that can stimulate cells of the innate immune system through a variety of transmembrane signaling systems (MAPK/ERK, AKT, JAK-STAT, etc.). This results in nuclear transcription of genes that produce such mediators as MMP-1, MMP-9 and RANKL, leading to joint damage.
Markers of protein degradation & tissue damage that are released into serum are characteristic & reproducible end points of specific pathologic processes.
14-3-3η is the only one of the seven isoforms that is highly upregulated in RA, present in serum and at even higher levels in synovial fluid. The 14-3-3η levels strongly correlate with levels of MMP-1 and MMP-3, and appear to be a marker for more severe disease with radiographic damage. In one study, ESR, CRP, RF, SCPA, HAQ and DAS were all more abnormal in patients who were 14-3-3η positive. Further, positivity and higher titers at baseline correlate with RP five years later. Serial testing shows that a decrease in 14-3-3η correlates with a response to treatment.
Finally, “protein fingerprinting” can quantitate levels of tissue destruction. Markers of protein degradation and tissue damage that are released into serum are characteristic and reproducible end points of specific pathologic processes. Degradation of Type I collagen offers a good example. There are several “fingerprints” of Type I collagen degradation. C1M is degradation product resulting from MMP-1 activity. ICTP, or C-terminal cross-linking telopeptide of Type I collagen, is also released from connective tissue as a result of MMP activity. CTX-1, or C-terminal telopeptide of Type I collagen, is a marker for bone resorption. By contrast, PINP, or N-propeptide of Type I collagen, is a marker for bone formation. Figure 2 (above) illustrates these protein fingerprints of Type I collagen.
