Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes

Abstract

Background:Intra-articular injection of hyaluronan (HA) has been suggested to have a disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms.Objective:To investigate the effects of HA species of different molecular mass, including 800 kDa (HA800) and 2700 kDa (HA2700), on the expression of aggrecanases (ie, ADAMTS species), which play a key role in aggrecan degradation.Methods:The effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin 1α (IL1α)-stimulated osteoarthritic chondrocytes were studied by reverse transcription PCR and real-time PCR. Expression of ADAMTS4 protein and aggrecanase activity and signal transduction pathways of IL1, CD44 and intracellular adhesion molecule 1 (ICAM1) were examined by immunoblotting.Results:IL1α treatment of chondrocytes induced ADAMTS4, and HA800 and HA2700 significantly decreased IL1α-induced expression of ADAMTS4 mRNA and protein. IL1α-stimulated aggrecanase activity in osteoarthritic chondrocytes was reduced by treatment with HA2700 or transfection of small interfering RNA for ADAMTS4. A similar result was obtained when HA2700 was added to explant cultures of osteoarthritic cartilage. HA2700 neither directly inhibited nor bound to ADAMTS4. Downregulation of ADAMTS4 expression by HA2700 was attenuated by treatment of IL1α-treated chondrocytes with antibodies to CD44 and/or ICAM1. The increased phosphorylation of IL1 receptor-associated kinase-1 and extracellular signal-regulated protein kinase1/2 induced by the IL1α treatment was downregulated by enhanced IRAK-M expression after HA2700 treatment.Conclusion:These data suggest that HA2700 suppresses aggrecan degradation by downregulating IL1α-induced ADAMTS4 expression through the CD44 and ICAM1 signalling pathways in osteoarthritic chondrocytes.

Effect of osteopontin on the mRNA expression of ADAMTS4 and ADAMTS5 in chondrocytes from patients with knee osteoarthritis

“…Previous studies investigating arthritis and OA with ADAMTS4/5 knockout mice have revealed that inhibition of ADAMTS5, but not ADAMTS4, mitigates aggrecan degradation and cartilage destruction, suggesting that ADAMTS5 has an important function in aggrecan degradation in mice (20)(21)(22). However, in human chondrocytes, ADAMTS4 is upregulated by interleukin (IL)-1, tumor necrosis factor α, oncostatin M and transforming growth factor β, indicating that ADAMTS4 functions as the primary aggrecanase in human OA cartilage (4,8,9,(23)(24)(25). The results of the present study, with regard to the mRNA expression of ADAMTS4 in human OA chondrocytes under monolayer culture, provide the first indications that OPN selectively inhibits ADAMTS4 expression, while the expression of ADAMTS5 is not affected by OPN.…”

“…Ariyoshi et al (36) demonstrated disruptive changes in chondrocyte-matrix interactions by HA oligosaccharides, which induced matrix degradation and elevated levels of aggrecanase (ADAMTS4 and ADAMTS5) activity via the NF-κB signaling pathway. Yatabe et al (4) observed that HA2700 (2,700 kDa HA) suppressed aggrecan degradation in OA chondrocytes via the downregulation of IL-1α-induced ADAMTS4 expression through the CD44 and intracellular adhesion molecule 1 signaling pathways. These results suggested that OPN may suppress aggrecanase degradation through the direct inhibition of ADAMTS4, by enhancing the binding of CD44 to HA.…”

“…Aggrecan is a major component of the cartilage-specific proteoglycans. A number of studies have indicated that the aggrecanase-mediated degradation of aggrecan is a crucial factor in the development of OA (4)(5)(6)(7). Aggrecanases are members of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, which includes ADAMTS1, 4, 5, 8, 9 and 15, that are expressed in the articular cartilage tissues and chondrocytes of numerous animal species, in addition to humans (8).…”

Oral Intake of a Liquid High-Molecular-Weight Hyaluronan Associated with Relief of Chronic Pain and Reduced Use of Pain Medication: Results of a Randomized, Placebo-Controlled Double-Blind Pilot Study

“…The direct immune modulating properties of HA are multifaceted and may happen through CD44-and/or ICAM-1 signaling pathways. 26 With respect to CD44/HA interaction, high-and low-molecular-weight forms of HA have different effects on CD44 clustering, signaling, and downstream cellular behavior such as adhesion. 11 The molecular weight of HA has direct impact on whether pro-or anti-inflammatory effects are prominent, including crosstalk between HA-mediated signaling and the COX-2/prostaglandin pathways.…”

Combination of High-Molecular-Weight Hyaluronic Acid and Cytokine Inhibitor Potently Inhibits Expression of Joint-Damage-Related Genes Induced By Synovial Fluid of RA Patients

“…The main mechanism through which HA prevents cartilage destruction and disease progression is thought to be its action in maintaining the viscoelastic properties of the synovial fluid [13]. In addition to this, we and others have reported that HA down-regulates the expressions of MMP (Matrix Metalloproteinase) and ADAMTS (A Disintegrin And Metalloproteinase With Thrombospondin Motifs), which are involved in the degradation of cartilage, and RANKL (Receptor Activator of NF-κBLigand), which is related to osteoclastogenesis, induced in synovial fibroblasts and chondrocytes by pro-inflammatory cytokines [14][15][16]. Moreover, intraarticular injection of HA is approved in Japan to reduce knee-joint pain in RA patients [17].…”