Abstract
IntroductionDevelopmental dysplasia of the hip (DDH) is a common musculoskeletal disorder that has pain and loss of joint function as major pathological features. In the present study, we explored the mechanisms of possible involvement and regulation of substance P (SP) and calcitonin gene-related peptide (CGRP) in the pathological and inflammatory processes of arthritis in DDH.MethodsBlood, synovial tissue and fluid samples were collected from patients diagnosed with different severities of DDH and from patients with femoral neck fracture. Levels of SP, CGRP and inflammatory cytokines in synovium and synovial fluid (SF) in the different groups were evaluated by immunohistochemistry, real-time PCR and enzyme-linked immunosorbent assay (ELISA). Correlations between neuropeptides and inflammatory cytokines in SF were evaluated by partial correlation analysis. The proinflammatory effects of SP and CGRP on synoviocytes obtained from patients with moderate DDH were investigated in vitro by real-time PCR and ELISA. The mechanisms of those effects were evaluated by Western blot analysis and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) DNA binding assay.ResultsSignificantly increased levels of neuropeptides and inflammatory cytokines were observed in synovium and SF from patients in the severe DDH group compared with the moderate DDH and control groups. In moderate DDH samples, SP in SF correlated with tumor necrosis factor (TNF)-α, and CGRP in SF correlated with TNF-α and interleukin (IL)-10. In the severe DDH group, SP in SF correlated with interleukin (IL)-1β, TNF-α and IL-10. CGRP in SF correlated with TNF-α. Additionally, SP might have had obvious proinflammatory effects on synoviocytes through the activation of NF-κB.ConclusionsThe upregulation of SP and CGRP in synovium and SF might participate in the inflammatory process of arthritis in DDH. The activation of the NF-κB pathway seems indispensable in the proinflammatory effect of SP on synoviocytes. This original discovery may indicate a potential clinical drug target and the development of innovative therapies for DDH.
Highlights
Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder that has pain and loss of joint function as major pathological features
Increased vascularization and neuropeptide expression in synovium and synovial fluid of patients with developmental dysplasia of hip During the progression from moderate to severe DDH, the hip joint synovium showed much more extensive vascularization and inflammatory cell infiltration, which were detected by Hematoxylin and eosin (H-E) staining (Figure 2A-C)
Levels of substance P (SP) and calcitonin gene-related peptide (CGRP) in the synovial fluid (SF) of patients with severe DDH increased significantly compared to levels in patients with moderate DDH (Figure 1E,F)
Summary
Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder that has pain and loss of joint function as major pathological features. We explored the mechanisms of possible involvement and regulation of substance P (SP) and calcitonin gene-related peptide (CGRP) in the pathological and inflammatory processes of arthritis in DDH. Shallow acetabulum, slacking joint capsule, narrowing joint space and disorder of the hip joint are the main anatomic features of DDH, which result in chronic pain, inflammation around the hip joint, synovial hyperplasia and hypertrophy in fossa acetabuli. Sensory nerve fibers in human labrum and synovium have been found to be immunoreactive with protein gene product 9.5, calcitonin gene-related peptide (CGRP) and tumor necrosis factor (TNF)-α in patients with hip pain or rheumatoid arthritis (RA) [6], suggesting the possible involvement and regulation of sensory nerves in the pathogenesis of hip pain
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