Attenuated Joint Tissue Damage Associated With Improved Synovial Lymphatic Function Following Treatment With Bortezomib in a Mouse Model of Experimental Posttraumatic Osteoarthritis

Abstract

Experimental PTOA is associated with decreased synovial lymphatic drainage, and increased M1 macrophages and inflammatory gene expression by LECs, which is improved by Btz. Intra-articular administration of Btz may present a new therapy for PTOA treatment, which is associated with improved synovial lymphatic function. This article is protected by copyright. All rights reserved.

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

“…Recent investigations suggest a contribution from circulating IgD + immature B lymphocytes and PRIME cells, as well as synovial macrophage populations (8,9). These novel observations are also consistent with our model of lymphatic dysfunction in RA flare 7, as: 1) the circulating IgD + B-cells may be the Bin cells that we observe within the lymphatic sinuses (20,21,35), 2) the circulating PDPN + PRIME cells may be lymphatic endothelial progenitors that are mobilized to repair damaged lymphatic vessels, and 3) the activated adherent macrophages in the lumen of degenerated PLVs (42) are likely from the afferent inflamed synovium (35,43).…”

“…We have focused on the synovial lymphatic system during arthritic progression and flare (10,12,16,20,25,26,35,43,44), and the effects of interventions that specifically target lymphatic contractions, whose physiologic importance in supporting lymphatic drainage and subsequent onset of lymphedema have been established in preclinical and clinical studies (7,29,45,46). We have also performed transmission electron microscopy studies on WT, Expanding and Collapsed PLVs (42).…”

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

“…Being ubiquitously expressed, these proteins represent a potential pharmacological target even though with several limitations [20]. To this regard, Bortezomib, a potent and clinically relevant proteasome inhibitor, is intermittently used for multiple myeloma treatment (MM) [21,22] and other inflammatory disease [23][24][25], in order to limit toxic effects [26]. In cells of hematopoietic origins, the classical proteasome is replaced by a different proteasome with an immunological role called immunoproteasome (IPs) [27].…”

Reduced lymphatic function contributes to age-related disease

“…A series of collaborative studies from the Schwarz and Xing groups have extensively detailed lymphatic involvement in several models of arthritis. They have demonstrated that inflammatory lymphangiogenesis and increased pumping initially facilitate the removal of immune cells and fluid to the draining lymph nodes, but that over time lymphatics regress and collecting lymphatic vessels lose contractility [3]. In their recent study of OA, blocking lymphangiogenesis accelerated joint tissue loss [3].…”

“…They have demonstrated that inflammatory lymphangiogenesis and increased pumping initially facilitate the removal of immune cells and fluid to the draining lymph nodes, but that over time lymphatics regress and collecting lymphatic vessels lose contractility [3]. In their recent study of OA, blocking lymphangiogenesis accelerated joint tissue loss [3]. The team identified increased pro-inflammatory macrophages in the knee joint and increased inflammatory markers expressed by lymphatic endothelial cells.…”