Proteinases and their receptors in inflammatory arthritis: an overview

Abstract

Proteinases are enzymes with established roles in physiological and pathological processes such as digestion and the homeostasis, destruction and repair of tissues. Over the past few years, the hormone-like properties of circulating proteinases have become increasingly appreciated. Some proteolytic enzymes trigger cell signalling via proteinase-activated receptors, a family of G protein-coupled receptors that have been implicated in inflammation and pain in inflammatory arthritis. Proteinases can also regulate ion flux owing to the cross-sensitization of transient receptor potential cation channel subfamily V members 1 and 4, which are associated with mechanosensing and pain. In this Review, the idea that proteinases have the potential to orchestrate inflammatory signals by interacting with receptors on cells within the synovial microenvironment of an inflamed joint is revisited in three arthritic diseases: osteoarthritis, spondyloarthritis and rheumatoid arthritis. Unanswered questions are highlighted and the therapeutic potential of modulating this proteinase-receptor axis for the management of disease in patients with these types of arthritis is also discussed.

Coagulopathies and inflammatory diseases: ‘…glimpse of a Snark’

“…Interestingly, the presence of autoantibodies against fibrinogen has been observed in patients with RA [106,107]. The role of coagulation in arthritis and its potential treatment through the targeting of PARs have been recently reviewed [108,109]. …”

A20: a master regulator of arthritis

“…Arthritis has long attracted much attention due to its multifaceted influence on human health; the three most common types are rheumatoid arthritis (RA), osteoarthritis (OA), and spondyloarthritis (SpA) [ 1 ]. RA, characterized by painful swollen joints and progressive bone erosion, is an autoimmune disease that severely impairs physical function and quality of life [ 2 ].…”

“…RA, OA, and SpA can be distinguished based on their diversity in pathogenesis and manifestations, but they demonstrate analogous inflammatory features; however, not all signs of inflammation appear in joints [ 1 ]. In addition, many inflammation-related pathways, such as the tumor necrosis factor receptor (TNFR)-induced nuclear factor kappa B (NF-κB) pathway, mitogen-activated protein kinase (MAPK) signaling, and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, are highly associated with these diseases [ 5 – 7 ].…”

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

“…Based on the human genome draft sequence, the main Cathepsin categories are serine (Cathepsin A and G), aspartic (Cathepsin D and E) and lysosomal cysteine proteases (Cathepsin B,C,F,H,K,L1,L2/V,O,S,W,X/Z) [4,5]. They have multiple functions, as one finds digestive proteases (present in saliva, stomach and intestines) for food processing inside the gastrointestinal tract (GIT), lysosomal proteases for intracellular housekeeping or caspases for transduction of one-way signal in apoptosis [6][7][8]. Interestingly, lysosomal Cathepsins (i.e., intracellular enzymes) have been widely involved in drug targeting as they require a slightly acidic environment to exhibit optimal enzymatic activity [9][10][11].…”