Abstract
Joint degeneration observed in the rat monoiodoacetate (MIA) model of osteoarthritis shares many histological features with the clinical condition. The accompanying pain phenotype has seen the model widely used to investigate the pathophysiology of osteoarthritis pain, and for preclinical screening of analgesic compounds. We have investigated the pathophysiological sequellae of MIA used at low (1 mg) or high (2 mg) dose. Intra-articular 2 mg MIA induced expression of ATF-3, a sensitive marker for peripheral neuron stress/injury, in small and large diameter DRG cell profiles principally at levels L4 and 5 (levels predominated by neurones innervating the hindpaw) rather than L3. At the 7 day timepoint, ATF-3 signal was significantly smaller in 1 mg MIA treated animals than in the 2 mg treated group. 2 mg, but not 1 mg, intra-articular MIA was also associated with a significant reduction in intra-epidermal nerve fibre density in plantar hindpaw skin, and produced spinal cord dorsal and ventral horn microgliosis. The 2 mg treatment evoked mechanical pain-related hypersensitivity of the hindpaw that was significantly greater than the 1 mg treatment. MIA treatment produced weight bearing asymmetry and cold hypersensitivity which was similar at both doses. Additionally, while pregabalin significantly reduced deep dorsal horn evoked neuronal responses in animals treated with 2 mg MIA, this effect was much reduced or absent in the 1 mg or sham treated groups. These data demonstrate that intra-articular 2 mg MIA not only produces joint degeneration, but also evokes significant axonal injury to DRG cells including those innervating targets outside of the knee joint such as hindpaw skin. This significant neuropathic component needs to be taken into account when interpreting studies using this model, particularly at doses greater than 1 mg MIA.
Highlights
Osteoarthritis (OA) is one of the most prevalent sources of chronic pain, affecting around 10% of men and 20% of women aged 60+ worldwide [1]
Consistent with previous studies, the timecourse of weightbearing asymmetry is biphasic, with asymmetry slightly correcting at the 7d timepoint but returning at 14d [6,10]
There was no difference in the degree of cartilage proteoglycan loss. 2 mg, but not 1 mg, MIA produced an increase in the expression of the injury marker ATF-3 in DRG cells, a reduction in intra-epidermal nerve fibre density within plantar epidermis, and ipsilateral spinal cord microgliosis, indicating significant neural injury
Summary
Osteoarthritis (OA) is one of the most prevalent sources of chronic pain, affecting around 10% of men and 20% of women aged 60+ worldwide [1]. The disabling effect of osteoarthritis is not due to altered joint biomechanics, such as locking and crepitation, and evoked and spontaneous pain associated with the arthritic joint [2]. MIA has been shown to inhibit chondrocyte metabolism, precipitating a rapid degeneration of joint integrity with features mirroring those seen clinically [5]. These include synovial thickening, loss of cartilage, formation of osteophytes and eventual fibrillation of cartilage. The inflammatory early phase of the model features joint swelling and immune cell infiltration of the patellar fat pad, and resolves fully by day 7 [9,10]
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