Toll-like receptors and their soluble forms differ in the knee and thumb basal osteoarthritic joints

Abstract

Background and purposeAlthough the pathogenesis of osteoarthritis (OA) is not well understood, chondrocyte-mediated inflammatory responses (triggered by the activation of innate immune receptors by damage-associated molecules) are thought to be involved. We examined the relationship between Toll-like receptors (TLRs) and OA in cartilage from 2 joints differing in size and mechanical loading: the first carpometacarpal (CMC-I) and the knee.Patients and methodsSamples of human cartilage obtained from OA CMC-I and knee joints were immunostained for TLRs (1–9) and analyzed using histomorphometry and principal component analysis (PCA). mRNA expression levels were analyzed with RT-PCR. Collected synovial fluid (SF) samples were screened for the presence of soluble forms of TLR2 and TLR4 by enzyme-linked immunosorbent assay (ELISA).ResultsIn contrast to knee OA, TLR expression in CMC-I OA did not show grade-dependent overall profile changes, but PCA revealed that TLR expression profiles clustered according to their cellular compartment organization. Protein levels of TLR4 were substantially higher in knee OA than in CMC-I OA, while the opposite was the case at the mRNA level. ELISA assays confirmed the presence of soluble forms of TLR2 and TLR4 in SF, with sTLR4 being considerably higher in CMC-I OA than in knee OA.InterpretationWe observed that TLRs are differentially expressed in OA cartilage, depending on the joint. Soluble forms of TLR2 and TLR4 were detected for the first time in SF of osteoarthritic joints, with soluble TLR4 being differentially expressed. Together, our results suggest that negative regulatory mechanisms of innate immunity may be involved in the pathomolecular mechanisms of osteoarthritis.

Toll-Like Receptors: Regulators of the Immune Response in the Human Gut

“…Soluble forms of TLR2 have been detected in human fluids such as breast milk, amniotic fluid, saliva [ 86 , 87 ], and in synovial fluid of human joints with osteoarthritis [ 88 ]. Intestinal epithelial cells also produce sTLR2.…”

Differential profiles of soluble and cellular toll like receptor 2 and 4 in chronic periodontitis

“…To date, four extracellular sTLRs have been identified in humans, including sTLR-1, sTLR-2, sTLR-4, and sTLR-6. Of these four extracellular sTLRs, sTLR-2 and sTLR-4 have been detected in most body fluids including saliva, serum, urine and breast milk (5–7).…”

“…To date thirteen mammalian TLRs and many of their ligands have been identified. In addition to membrane-associated TLRs, soluble forms of TLRs (sTRLs) have been identified in serum, urine, tears and saliva (5–7). sTLRs are thought to act as negative regulators and inhibit TLR mediated signaling_pathways.…”

Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

“…Moreover, functional studies have demonstrated that primary FLS from healthy and OA patients express TLRs, which actively respond to several DAMP ligands, such as tenascin-C or S100A8/A9 [20,21]. In the OA synovial fluid TLR4 is also present in the soluble form, and it is associated with the OA severity, making sTLR4 an intriguing biomarker [22,23]. TLRs activation and the ensuing NF-kB activation is followed by the production of chemokines (e.g., IL-8 and CCL5) and cytokines (e.g., IL-1, IL-6, and TNF) which participate in the recruitment of macrophages, granulocytes, and lymphocytes cell into the synovium of OA patients [24].…”

“…All TLRs are present in articular cartilage and are known to be upregulated in OA cartilage, particularly in the lower limbs such as knee and hip cartilage [38]. However, a recent study indicated that there are also joint-specific TLR expression patterns, particularly between hand and knee OA, which might also implicate differential immune mechanisms of large and small joints in OA [23].…”