Pathways of Microvascular Permeability in the Synovium of Normal and Diseased Human Knees

Abstract

Objective.Our study uses the entire proteomes of serum and synovial fluid (SF) to characterize the avenues of microvascular egress of plasma proteins, and quantifies that traffic in normal and diseased human knees.Methods.Paired aliquots of serum and SF were collected from 17 knees of 11 subjects who died without evident joint disease and 16 patients with clinical effusions, fractionated by gel filtration chromatography and analyzed as continuous plots of the SF/serum concentration ratio versus molecular radius from 1 to 12 nanometers (nm). Curve-stripping methodology, a 3-pore model, and known protein kinetics were then applied to estimate the dimensions of and the net outflow through fenestral, “small,” and “large” apertures in the microvascular endothelium.Results.The 3-pore model correlated highly with the observed data (r = 0.992 in normal and 0.980 in arthritis), yielding the following mean values: for the fenestra, the normal radius (nm) was 1.75 and the effused 3.5, and the normal flow (μl/min) was 1.74 and the arthritic 22.0; for the small pore, the normal radius was 8.6 and the effused 8.5, and the normal flow was 1.5 and the arthritic flow 9.1; for the large pore, the normal radius was 40 and the effused 36, and the normal flow was 0.24 and the arthritic flow 15.5.Conclusion.These findings provide the first functional definition of synovial, endothelial fenestrae; reveal that the “increased vascular permeability” of inflammation is not limited to interendothelial gaps; present evidence suggesting that glycocalyceal damage and aquaporin upregulation may affect permeability in arthritic synovium; and define a straightforward methodology for interpretation of biomarker concentrations in arthritic SF.