Beta-defensins are broad-spectrum antimicrobial peptides (APs) that are components of innate immunity. Recent investigations showed the induction of beta-defensins in synovial membranes of osteoarthritic (OA) joints and suggested that they have functions other than the ability to kill microbes. As a result of these findings, we undertook this study to investigate the production of human beta-defensin 3 (HBD-3) in OA cartilage and to determine its influence on chondrocyte function.
Healthy and OA cartilage were assessed for HBD-3 expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. HBD-3 expression in C28/I2 chondrocytes after administration of tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) was determined by real-time RT-PCR and immunodot blot. Enzyme-linked immunosorbent assay experiments were used to study the effects of HBD-3 in cultured articular chondrocytes and in healthy and OA cartilage discs. Immunohistochemical analyses were performed to study the expression of mouse beta-defensins (MBDs) in OA cartilage of STR/Ort mice.
HBD-3 was induced in OA cartilage without bacterial challenge. Cytokines involved in the pathogenesis of OA, namely, TNFalpha and IL-1, were strong inducers of HBD-3 in cultured chondrocytes. Application of the recombinant HBD-3 protein to cultured chondrocytes and cartilage discs resulted in increased production of cartilage-degrading matrix metalloproteinases and in down-regulation of their endogenous regulators, tissue inhibitors of metalloproteinases 1 and 2. Furthermore, STR/Ort mice, which are genetically predisposed to develop OA-like lesions in the knee joint, demonstrated an increased expression of MBDs 3 and 4 in cartilage compared with that in healthy animals.
These findings widen our knowledge of the functional spectrum of APs and demonstrate that HBD-3 is a multifunctional AP with the ability to link host defense mechanisms and inflammation with tissue-remodeling processes in articular cartilage. Moreover, our data suggest that HBD-3 is an additional factor in the pathogenesis of OA.