Effect of Human Synovial Fluid From Osteoarthritis Patients and Healthy Individuals on Lymphatic Contractile Activity

Abstract

The lymphatic system has been proposed to play a crucial role in preventing the development and progression of osteoarthritis (OA). As OA develops and progresses, inflammatory cytokines and degradation by-products of joint tissues build up in the synovial fluid (SF) providing a feedback system to exacerbate disease. The lymphatic system plays a critical role in resolving inflammation and maintaining joint homeostasis, however, there is evidence that the lymphatics can become dysfunctional during OA. We hypothesized that the functional mechanics of lymphatic vessels (LVs) draining the joint could be directly compromised due to factors within SF derived from OA patients (OASF). Here, we utilized OASF and SF derived from healthy individuals (HSF) to investigate effects of SF entering the draining lymph on migration of lymphatic endothelial cells (LECs) in vitro, and lymphatic contractility of rat femoral LVs (RFLVs) ex vivo. Dilutions of OASF and HSF led to an increased migratory response in vitro compared to LECs treatment with media without serum. Ex vivo, OASF and HSF treatments were administered within the lumen of isolated LVs under controlled pressures. OASF treatment transiently enhanced the RFLVs tonic contractions while phasic contractions were significantly reduced after 1 hr of treatment and complete ceased after overnight treatment. HSF treatment on the other hand displayed a gradual decrease in lymphatic contractility (both tonic and phasic contractions). The observed variations after SF treatments suggest the pump function of LV draining the joint could be directly compromised in OA and thus might present a new therapeutic target.

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“…They also showed that MetSyn conditions diminish eNOS expression, thereby affecting the flow‐mediated changes in lymphatic function 71 . Michalaki et al 72 used rat isolated contracting collecting vessels to reveal the effect of osteoarthritis, a condition that leads to inflammation, on lymphatic contractile activity, and showed that the pumping function of the lymphatic vessel draining the joint can be significantly compromised in osteoarthritis leading to the possibility of investigating novel therapeutics. Also, connecting canulated popliteal lymph vessels from TNF‐transgenic mice to a wide range of hydrostatic pressures showed that inflammatory arthritis significantly reduces pumping amplitude, ejection fraction, and fractional pump flow 49 .…”

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“…Additionally, there is a negative correlation between lymphatic vessel density and synovial effusion, which is a characteristic feature of advanced stages of OA development 50 . The reduced lymphatic vessel density may contribute to the retention of synovial fluid in OA patients, potentially exacerbating joint inflammation by impairing lymphatic pumping function 116 . In addition to the number of lymphatic vessels, the relationship between the severity of OA and the number, size, and central fatty changes of DLNs observed in MR images of patients does not exhibit a linear trend 117 .…”