Osteochondral angiogenesis and increased protease inhibitor expression in OA

SummaryObjectiveNormal cartilage is resistant to vascular invasion and anti-angiogenic protease inhibitors may contribute to its avascular status. We hypothesized that dysregulated expression of four key anti-angiogenic protease inhibitors may contribute to increased osteochondral vascularity in osteoarthritis (OA).DesignMedial tibial plateaux from OA patients (n=40) were compared with those from non-arthritic controls collected post-mortem (PM, n=10). Immunohistochemistry was performed for protease inhibitors TIMP-1, TIMP-3, PAI-1 and SLPI and the pro-angiogenic factor vascular endothelial growth factor (VEGF). Immunoreactivity in articular chondrocytes was scored. Chondropathy was measured as a modified Mankin score, and osteochondral vascular density as number of channels crossing each mm of tidemark. Non-parametric analyses were used for all data.ResultsAll protease inhibitors and VEGF were localised to chondrocytes near the articular surface, less often in the middle zone, and rarely to deep chondrocytes. Scores for VEGF, TIMP-1, TIMP-3, SLPI and PAI-1 were all increased in OA compared with PM, and higher scores were associated with greater chondropathy. Chondrocyte expression of VEGF was associated with higher osteochondral vascular density (r=0.32, P<0.05), whereas protease inhibitors were not.ConclusionsThe resistance of normal articular cartilage to vascular invasion may be more due to its matrix environment than ongoing protease inhibitor expression. Upregulation of protease inhibitors by superficial chondrocytes in OA may moderate the angiogenic effects of growth factors such as VEGF. However, failure of deep chondrocytes to express anti-angiogenic protease inhibitors may permit vascular invasion into the articular cartilage

Relationship between structural pathology and pain behaviour in a model of osteoarthritis (OA)

Objectives To address the hypothesis that different types of established OA pain behaviours have associations with different aspects of articular pathology, we investigated the relationship between structural knee joint pathology and pain behaviour following injection of a low versus a high dose of monosodium iodoacetate (MIA) in the rat. Methods Rats received a single intra-articular injection of 0.1mg or 1mg MIA or saline (control). Pain behaviour (hind limb weight bearing asymmetry (WB) and hindpaw withdrawal threshold (PWT) to punctate stimulation) was assessed. Cartilage and synovium were examined by macroscopic visualisation of articular surfaces and histopathology. Results Both doses of MIA lowered PWTs, 1mg MIA also resulted in WB asymmetry. Both doses were associated with cartilage macroscopic appearance, proteoglycan loss, abnormal chondrocyte morphology, increased numbers of vessels crossing the osteochondral junction, synovitis and macrophage infiltration into the synovium. PWTs were more strongly associated with chondrocyte morphology, synovitis and macrophage infiltration than with loss of cartilage surface integrity. Conclusions Both pain behaviours were associated with OA structural severity and synovitis. Differences in pain phenotype following low versus higher dose of MIA were identified despite similar structural pathology. OA structural pathology as traditionally measured only partially explains the MIA-induced pain phenotype

The anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain

Objective: Nerve growth factor (NGF) has a pivotal role in peripheral hyperalgesia and inflammation; anti-NGF antibodies attenuate pain responses in inflammatory pain models, and in people with osteoarthritis (OA) or low back pain. The aim of this study was to characterise the peripheral mechanisms contributing to the analgesic effects of anti-NGF antibody treatment in an established model of joint pain, which mimics key clinical features of OA. Design: Effects of preventative vs therapeutic treatment with an anti-NGF antibody (monoclonal antibody 911: muMab 911 (10 mg/kg, s.c.)) on pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWT)), cartilage damage, synovitis and numbers of subchondral osteoclasts were investigated in the monosodium iodoacetate (MIA) model. Potential direct effects of NGF on receptor activator of nuclear factor kappa-B ligand (RANKL) mediated osteoclastogenesis were investigated in cultured human osteoclasts. Results: Intra-articular MIA injection resulted in significant pain behaviour, cartilage damage, synovitis and increased numbers of subchondral osteoclasts. Both preventative and therapeutic treatment with muMab 911 significantly prevented, or reversed, MIA-induced pain behaviour, but did not alter cartilage or synovial pathology quantified at the end of the treatment period. NGF did not facilitate RANKL driven osteoclast differentiation in vitro, but preventative or therapeutic muMab 911 reduced numbers of TRAP positive osteoclasts in the subchondral bone. Conclusions: We demonstrate that anti-NGF antibody treatment attenuates OA pain behaviour despite permitting cartilage damage and synovitis. Indirec