A hexadecylamide derivative of hyaluronan (HYMOVIS®) has superior beneficial effects on human osteoarthritic chondrocytes and synoviocytes than unmodified hyaluronan

Abstract

BackgroundIntra-articular hyaluronan (HA) injection provides symptomatic benefit in the treatment of osteoarthritis (OA). Previously we found superior beneficial effects in a large animal OA model of a hexadecylamide derivative compared with unmodified HA of the same initial molecular weight. The current study sought to define possible molecular mechanisms whereby this enhanced relief of symptoms was occurring.MethodsChondrocytes and synovial fibroblasts were isolated from tissues of patients undergoing arthroplasty for knee OA. Monolayer cultures of cells were treated with 0, 0.5, 1.0 or 1.5 mg/mL of unmodified HA (500–730 kDa) or a hexadecylamide derivative of HA of the same initial molecular weight (HYADD4®-G; HYMOVIS®) simultaneously or 1 hour before incubation with interleukin (IL)-1beta (2 ng/mL). Cultures were terminated 15 or 30 minutes later (chondrocytes and synovial fibroblasts, respectively) for quantitation of phosphorylated-(p)-JNK, p-NFkappaB, p-p38, or at 24 hours for quantitation of gene expression (MMP1 &13, ADAMTS4 &5, TIMP1 &3, CD44, COL1A1 &2A1, ACAN, PTGS2, IL6, TNF) and matrix metalloproteinase (MMP)-13 activity.ResultsThe hexadecylamide derivative of HA had significantly better amelioration of IL-1beta-induced gene expression of key matrix degrading enzymes (MMP1, MMP13, ADAMTS5), and inflammatory mediators (IL6, PTGS2) by human OA chondrocytes and synovial fibroblasts. Pre-incubation of cells with the derivatized HA for 1 hour prior to IL-1beta exposure significantly augmented the inhibition of MMP1, MMP13, ADAMTS4 and IL6 expression by chondrocytes. The reduction in MMP13 mRNA by the amide derivative of HA was mirrored in reduced MMP-13 protein and enzyme activity in IL-1beta-stimulated chondrocytes. This was associated in part with a greater inhibition of phosphorylation of the cell signalling molecules JNK, p38 and NF-kappaB.ConclusionsThe present studies have demonstrated several potential key mechanisms whereby the intra-articular injection of a hexadecylamide derivative of HA may be acting in joints with OA.

Specific concentration of hyaluronan amide derivative induces osteogenic mineralization of human mesenchymal stromal cells: Evidence of RUNX2 and COL1A1 genes modulation

“…Different formulations of HA are produced and crosslinking strategies are used to control HA degradation and mechanical properties. An hyaluronan amide derivative (HAD) of 500–730 kDa has been produced via amidation of the polymer carboxyl groups by long chain alkylamine (98% remains unmodified HA) to enhance the rheological properties and to increase the residence time in the joint cavity compared with non‐amidated unmodified HA (HYAL; Smith, Russell, Schiavinato, & Little, ).…”

Changes in Knee Joint Space Width in Treatment with a New Hyaluronic-Based Hydrogel

“…A frequently encountered debate in the literature addresses the molecular weight (MW) of the HA product injected. It was previously demonstrated that HA products with a MW of 500-730 kDa pass easily through the synovial membrane stimulating the endogenous synthesis of HA [23]. It is also specified that this may lead to a large quantity of high molecular HA to be secreted in the synovial liquid [24].…”

Reduced Analgesics Consumption and Pain Intensity after Injections with a New Hyaluronic Acid in Patients with Knee Osteoarthritis

“…VAS is a consistent and validated instrument in measuring chronic pain intensity [21,22,23]. As 38% of Mures population consists of Hungarians [24], the questionnaires used in the study were translated into two languages: Romanian and Hungarian.…”