Lactobacillus casei enhances type II collagen/glucosamine-mediated suppression of inflammatory responses in experimental osteoarthritis
Introduction
Osteoarthritis (OA) is a chronic joint disease characterized by progressive cartilage degeneration, synovial inflammation, subchondral bone sclerosis, and osteophyte formation (Hayami et al., 2006, Lohmander, 2000). Although molecular characterization OA pathogenesis has remained elusive, it mainly affects weight-bearing joints such as knees and hips. OA patients suffer from diverse symptoms including chronic pain, stiffness, and limited movement (Sarzi-Puttini et al., 2005).
In OA patients, chronic inflammatory responses occur in synovial membranes with increased expression of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) along with mononuclear cell infiltration (Benito et al., 2005). Inflammatory cytokines produced by synovial cells, chondrocytes, and mononuclear cells are the main contributors to the progression of OA by increasing expression of matrix metalloproteinases (MMPs) (Fernandes et al., 2002). A complex network of cytokines and proteolytic enzymes leads to degradation of the extracellular matrix (ECM) proteins of cartilage such as type II collagen (CII), proteoglycans, and hyaluronic acid (Rengel et al., 2007). These biochemical changes also inhibit synthesis of ECM molecules in chondrocytes which are required for restoring degraded cartilage. However, anti-inflammatory cytokines such as IL-4, IL-10 or IL-13 suppress the synthesis of IL-1β and TNF-α in OA tissues (Alaaeddine et al., 1999). Therefore, modulation of cytokine expression is considered as a potential therapeutic strategy for OA through the regulation of inflammatory responses and proteolytic pathways (Jovanovic et al., 1998).
Currently, there is no effective disease-modifying treatment targeting pain reduction, suppression of inflammation, and improvement of joint function in OA (Combe et al., 2004). Most OA treatments are based on symptomatic pain relief and accompanied diverse side-effects which restricts their use (Hungin and Kean, 2001). However, dietary supplements such as glucosamine (Gln) and chondroitin sulfate are widely used by OA patients without generating side effects. Both dietary supplements have shown cartilage-protective effects and improvement of OA symptoms (McAlindon et al., 2000). Gln is the metabolic precursor required for the synthesis of ECM components (Gouze et al., 2006). However, several studies suggested that Gln could not effectively modulate OA pathogenesis in the clinical trial setting (Clegg et al., 2006, Sawitzke et al., 2008). We previously showed that Lactobacillus casei (L. casei) suppressed rheumatoid arthritis (RA) by down-regulating Th1-type inflammatory responses (So et al., 2008a). Oral administration of L. casei with CII potentiated induction of CII-specific oral tolerance by enhancing population of Foxp3+CD4+ T cells (So et al., 2008b). Although beneficial effects of probiotics on a variety of inflammatory diseases have been described, no information is available about the effect of probiotics on OA.
In the present study, we investigated whether L. casei can suppress OA progression by examining inflammatory responses elicited in monosodium iodoacetate (MIA)-induced experimental OA models. MIA model mimics severe and acute OA pain and shows histopathology of the degenerating joint, which is similar with human OA (Combe et al., 2004, Janusz et al., 2001). Intra-articular injection of MIA induces initial inflammatory responses with infiltration of macrophages, neutrophils, and lymphocytes (Bove et al., 2003). Then, damaged subchondral bones are exposed at the later stages, thereby inducing joint pain (Janusz et al., 2001). The MIA model shows distinct sensitivity to pharmacological intervention with an early cyclooxygenase (COX)-sensitive phase and a later COX-insensitive phase (Ivanavicius et al., 2007). We found that co-administration of L. casei with CII/Gln more effectively suppressed OA pathogenesis compared to rats treated with Gln alone. These results are accompanied by decreased expression of pro-inflammatory cytokines in CD4+ T cells, synovial fibroblasts, and chondrocytes. Our study provides evidence that L. casei can be a potent nutraceutical modulator for OA treatment.
Section snippets
Animal models of OA
Female Wistar rats, 6 to 8 weeks of age, were purchased from SLC Inc. (Shizuoka, Japan) and maintained under specific pathogen-free conditions in the animal facility of Gwangju Institute of Science and Technology (GIST). The animal experiments were approved by the GIST Animal Care and Use Committee. Experimental OA was induced with monosodium iodoacetate (MIA) by intra-articular injection as described previously (Guingamp et al., 1997). Rats were anesthetized with ketamine hydrochloride (50
Oral administration of L. casei enhances suppressive effect of CII/Gln on experimental osteoarthritis
The main purpose of this study was to evaluate whether oral administration of L. casei with CII/Gln can exert a therapeutic effect by suppressing the pathogenesis of OA, and to elucidate its therapeutic mechanisms. Wistar rats were assigned to one of the five groups and oral-administration was initiated 14 days before MIA injection and continued for 8 weeks as described in method (Fig. 1A). We first assessed effects of L. casei on the symptoms associated with MIA-induced OA model. One of the most
Discussion
Osteoarthritis is the most common joint disorder in old aged people, but the underlying pathogenic mechanism and precise cause of it remain unknown (Sarzi-Puttini et al., 2005). Currently, most treatments for OA are analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), which have side effects including gastric and cardiovascular problems (Ray et al., 2004). The dietary supplements, Gln and chondroitin sulfate, have been widely used to treat OA (McAlindon et al., 2000). However, their
Conclusion
In the present study, we have shown that oral administration of L. casei with CII/Gln synergistically suppressed arthritic inflammation in OA. Our results suggest that L. casei can be a potent neutraceutical modulator for OA treatment.
Conflict of interest statement
The authors declare that they have no potential conflicts of interest including any financial and personal relationships with other people or organizations.
Acknowledgements
We thank Darren Reece Williams for critical proof reading of this manuscript. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A080630).
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