UC San Diego
Biophysical Mechanisms of Disturbances to Synovial Joint Lubricant Homeostasis in Post-Traumatic Osteoarthritis
- Author(s): Raleigh, Aimee
- Advisor(s): Sah, Robert L
- Firestein, Gary S
- et al.
Post-traumatic osteoarthritis (PTOA) progression in synovial joints involves the individual and interactive responses of multiple cell types in articular cartilage (AC) and synovial lining (SL), resulting in alterations in the concentration of functional lubricant molecules, hyaluronan (HA) and proteoglycan 4 (PRG4) in synovial fluid (SF). We hypothesize that changes in lubricant concentration during disease progression are due to both biophysical and biological processes in the synovial joint. This dissertation aimed to analyze these processes, in a rabbit model of PTOA and in response to selected therapies, using a multi-scale mathematical model, using estimates for in vivo lubricant secretion and macromolecular transport properties.
Previous mass balance analyses were extended to model the dependence of SF HA and PRG4 concentrations on rates of lubricant generation, loss, clearance, and SF volume fluxes. Compared to contralateral non-operated (Non-OP) and healthy control (CTRL) joints, ACL-transected (ACLT) knees had lower SF concentrations of both HA and PRG4 at extended times following injury, attributable to distinct biological and biophysical phenomena. Despite increased HA generation by cells in the SL, HA concentration was decreased at both acute and chronic times in ACLT knees due to increased loss and clearance rates, as well as increased SF volume (diluting the HA in SF). PRG4 concentrations were decreased only at extended times post-injury, due to a substantial reduction in the rates of PRG4 synthesis by cells in the SL and AC, in addition to dilution effects of SF effusions. One potential mechanism of increased lubricant loss following acute injury is altered SL transport. An increase in the ratio of protein in SF to that in serum, kSF:S, was correlated with a decreased HA concentration, and particularly with decreased HA of high molecular mass. The increases in kSF:S suggest that changes to SL architecture following injury (such as that stemming from increased cellular proliferation, matrix reorganization, and stretching due to joint swelling) may impact its permeability to large molecules, such as HA and PRG4. When viscosupplement therapies were applied in three serial injections following ACLT, the decreases in lubricant concentrations were reversed, due to increased lubricant secretion as well as maintenance of SL macromolecular retention (attenuated kSF:S).
The refinement of a multi-scale model that mechanistically describes variations in SF lubricant concentrations using in vivo rabbit data can serve as a foundation for better understanding the basis for SF dynamics, as well as elucidating timeframes in which an intervention may reverse progressive joint degradation. The modeling indicates that metrics and markers of synovial joint health need to include not only biological indices at the levels of cells (biosynthesis) and molecules (causing degradation), but also physical properties of tissues (membrane permeability) and organs (fluid flux).