Introduction. NF-κB transcription factors regulate a number of genes that are activated under stress conditions. Blockage of the the canonical NF-κB pathway has been emerged as a possible strategy to cure osteoarthritis and rheumatoid arthritis. However, the roles of κNF-B in normal skeletal physiology are largely unknown owing to the lack of suitable animal models. Here, we investigated the function of canonical κNF-B pathway in the cartilaginous skeleton by ablating Nemo (NF-κB essential modulator) in chondrocytes using the Col2a1 transgene. Methods. Mice were analyzed by skeletal staining, histology, proliferation and apoptosis assays at various stages. Histochemistry, GAG assay and immunohistochemistry were utilized to assess the impact of NEMO-deficiency in cytokine-induced cartilage degradation of hip explants. To identify genes regulated through the canonical NF-κB pathway in response to injury, an ex vivo hip avulsion model was applied. 24 genes known to be induced early following cartilage injury were assessed in wildtype and mutant hips by RT-PCR. Time lapse photography was used to investigate chondrocyte migration in vitro. Atomic force microscopy (AFM) was applied to assess biomechanical properties of the cartilage. Pathological changes of articular cartilage were scored in aged joints. Results. Mutant mice exhibited moderate dwarfism postnatally characterized by disorganized growth plate, abnormal chondrocyte proliferation, apoptosis and migration. AFM indentation experiments showed no changes in biomechanical properties of the mutant growth plate compared with control. Exposure of aggrecan degradation neoepitopes and release of GAGs were less pronounced in mutant hip explants stimulated by cytokines. Of the 24 genes regulated 4h following injury in wildtype hips, only Arginase-1 was suppressed in the mutant hips, while the expression levels of most other inflammatory response genes e.g. TSG-6, NOS2, COX2, IL6 and IL1b were unaffected. A small number of genes, IL-18, MMP-3 and Has-2 were further upregulated upon injury in Nemo-deficient compared with wildtype hips.
Osteoarthritis (OA) is an important cause of
pain, disability and economic loss in humans, and is similarly important in
the horse. Recent knowledge on post-traumatic OA has suggested opportunities
for early intervention, but it is difficult to identify the appropriate
time of these interventions. The horse provides two useful mechanisms
to answer these questions: 1) extensive experience with clinical
OA in horses; and 2) use of a consistently predictable model of
OA that can help study early pathobiological events, define targets
for therapeutic intervention and then test these putative therapies.
This paper summarises the syndromes of clinical OA in horses including
pathogenesis, diagnosis and treatment, and details controlled studies
of various treatment options using an equine model of clinical OA.