ABSTRACT
BACKGROUND: We have reported that a single intra-articular injection of diclofenac etalhyaluronate (SI-613) exerted a potent and long-lasting analgesic effect in experimental arthritis models. In the present study, we investigated the effect of SI-613 on the production of high molecular weight hyaluronic acid (HMW-HA) in synoviocytes from osteoarthritis (OA) patients and compared its efficacy with that of hyaluronic acid (HA). METHODS: We compared the effect of SI-613, HA, and diclofenac sodium (DF-Na) on high molecular weight HA production by human synoviocytes. RESULTS: SI-613 and exogenous HA induced the production of high molecular weight HA in synoviocytes from OA patients, whereas DF-Na had no effect. The molecular weight of newly produced HA was about 1000 kDa in the HA-treated synoviocytes and much higher than 2400 kDa in the SI-613-treated cells. The effect of the mixture of HA and DF-Na was similar to that of HA alone in that the molecular weight of newly produced HA was around 1000 kDa. SI-613 significantly suppressed hyaluronidase 2 (HYAL2) mRNA expression and significantly enhanced hyaluronan synthase 2 (HAS2) mRNA expression. HA had no effect on the expression levels of HYAL and HAS. CONCLUSION: The present results clearly demonstrate that SI-613 induces the production of high molecular weight HA in synoviocytes from OA patients, suggesting the long-lasting analgesic and disease modifying effect of SI-613 for OA. Taken together with the anti-inflammatory and analgesic effects we recently reported for the intra-articular administration of SI-613 to experimental animal models, SI-613 holds great promise for the treatment of knee osteoarthritis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Diclofenac/analogs & derivatives , Diclofenac/pharmacology , Hyaluronic Acid/analogs & derivatives , Hyaluronic Acid/metabolism , Synoviocytes/drug effects , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Cell Adhesion Molecules/antagonists & inhibitors , Cell Adhesion Molecules/metabolism , Cells, Cultured , Diclofenac/therapeutic use , Drug Evaluation, Preclinical , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/metabolism , Humans , Hyaluronan Synthases/metabolism , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Hyaluronoglucosaminidase/antagonists & inhibitors , Hyaluronoglucosaminidase/metabolism , Injections, Intra-Articular , Molecular Weight , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Primary Cell Culture , Synoviocytes/metabolismABSTRACT
Heparin binds various growth factors and activates them to interact with high-affinity cell surface receptors; a specific array of sulfate groups in the heparin backbone structure is very important for this interaction. In the present study, we evaluated the effects of two novel heparin derivatives, 6-O-desulfated heparin (6-DSH) and 2-O-desulfated heparin (2-DSH), on blood coagulation and the proliferation of human neural stem/progenitor cells (NSPCs). 6-DSH showed lower anticoagulant activity than intact heparin or 2-DSH, as measured by the activated partial thromboplastin time and thrombin time. In the presence of FGF-2, 6-DSH and 2-DSH promoted approximately the same rate of proliferation of human NSPCs, without noticeably changing the expression of nestin. The mitotic effects of 6-DSH and 2-DSH on human NSPCs were different from their effects on mouse hematopoietic stem cells and fibroblasts. These findings indicate that 6-DSH and 2-DSH have the same ability to promote the growth of human NSPCs as intact heparin. Our results suggest that these two novel heparin derivates, especially 6-DSH, could be used in clinical applications for ex vivo human NSPC culture, as a lower-risk growth co-adjuvant than intact heparin.
