Background: Abnormal activation of sonic hedgehog (SHH) signaling has been found in synovium from patients with rheumatoid arthritis (RA). Inhibition of SHH signaling is reported to attenuate inflammation and cartilage damage in adjuvant-induced arthritis (AIA). Previously we have demonstrated that SHH signaling promoted the tumor-like behavior of fibroblast-like synoviocytes (FLSs) through p38 MAPK in vitro .

Objectives: In the current study, we aim to further explore the role of SHH-p38 MAPK signaling in regulating synovial hyperplasia and bone erosion in experimental arthritis.

Methods: Collagen-induced arthritis (CIA) mouse model was induced and the mice were injected with adenovirus associated virus (AAV) overexpressing SHH or treated with small molecule inhibitors GDC-0449. SB203580 was administrated for the inhibition of p38 MAPK. The severity of paw inflammation was graded and serum levels of TNFα, IL-6 were detected. The histological features of arthritis were evaluated by H&E staining. The bone erosion was identified by micro-CT assessment and the number and function of osteoclasts were determined.

Results: Blockade of SHH by GDC-0449 significantly alleviated the symptoms and decreased the synovial hyperplasia, inflammatory infiltration, cartilage and bone damage in ankles of CIA. The bone erosions in the area of the metatarsophalangeal and ankle joints and production of TNFα, IL-6 were decreased by SHH inhibition. In addition, the administration of GDC-0449 significantly decreased the number of TRAP positive cells and the expression of NFATc1. On the contrary, SHH overexpression led to increased severity of arthritis and pathological changes. We also observed the accelerated bone injury accompanied with increased number and activity of osteoclasts and increased production of serum IL-6 in mice with upregulation of SHH expression. Of note, the administration of p38 MAPK inhibitor reversed the effects of SHH overexpression, with a reduction of joint swelling and histological scores. Inhibition of p38 MAPK prevented the bone erosion and decreased the number of TRAP positive cells and the expression of NFATc1, which were promoted by SHH overexpression.

Conclusion: The study indicates that SHH promotes the synovial hyperplasia and bone erosion of CIA in a p38 MAPK-dependent manner. SHH-p38 MAPK signaling could be a potential target for the treatment of RA.

Acknowledgments: This work was supported by grants from the National Natural Science Foundation of China (81571584, 81701609).

Disclosure of Interests: None declared