Human β‐defensin 3 mediates tissue remodeling processes in articular cartilage by increasing levels of metalloproteinases and reducing levels of their endogenous inhibitors

Abstract

Objective Beta‐defensins are broad‐spectrum antimicrobial peptides (APs) that are components of innate immunity. Recent investigations showed the induction of β‐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 β‐defensin 3 (HBD‐3) in OA cartilage and to determine its influence on chondrocyte function. Methods 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 α (TNFα) 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 β‐defensins (MBDs) in OA cartilage of STR/Ort mice. Results HBD‐3 was induced in OA cartilage without bacterial challenge. Cytokines involved in the pathogenesis of OA, namely, TNFα 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. Conclusion 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.