Abstract
Purpose: To investigate the effect of the hedgehog (Hh) pathway inhibitor, cyclopamine, and activator purmorphamine on articular cartilage cell proliferation.
 Methods: Rats were subjected to AA and CIA models. Secondary paw swelling was measured at 12, 15, 18, 21, 24, 27, and 30 days. The rats were sacrificed on day 30. Tissues from the cartilage and knee joints were collected. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay while cell apoptosis was determined by annexin V-fluorescein isothiocyanate/propidium iodide assay. Protein expression levels of Shh, Ptch1 and Gli1 were determined by Western blotting.
 Results: Compared with the control group, arthritis index and secondary foot swelling of the adjuvant arthritis (AA) and collagen-induced arthritis (CIA) groups deteriorated significantly (p < 0.05). MTT data revealed that cyclopamine promoted articular cartilage cell proliferation of the AA and CIA groups. The cell proliferation rates of AA and CIA groups were significantly higher than that of control group (p < 0.05). Flow cytometry showed that the cell apoptosis rates of AA and CIA groups were significantly lower than that of control group (p < 0.05). Compared with control, cyclopamine decreased the protein expression levels of sonic Hh, patched homologue 1 and glioma-associated oncogene homologue, but the effect of purmorphamine was the reverse.
 Conclusion: Hh pathway inhibitor (cyclopamine) and activator (purmorphamine) affect the expression of Hh pathway. Disruption of the Hh pathway may be of potential therapeutic significance in protecting articular cartilage from rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease leading to the symptoms like synovial inflammation, bone erosion, and cartilage destruction [1]
The present study investigated the expression of the Hh signal pathway in the blood, synovial cells, and chondrocytes of an adjuvant arthritis (AA) rat model and a collagen-induced arthritis (CIA) rat model
In AA and CIA groups, 20 μmol/L of cyclopamine induced the highest level of cell proliferation (1.24 ± 0.11, p < 0.05) and (1.14 ± 0.11, p < 0.05), respectively
Summary
Rheumatoid arthritis (RA) is an autoimmune disease leading to the symptoms like synovial inflammation, bone erosion, and cartilage destruction [1]. Almost all RA patients eventually develop varying degrees of joint dysfunction that poses great threat to human health [2]. The incidence of RA is approximately 1 %. The pathogenesis of RA is largely unknown, it is recognized that synoviocyte proliferation and inflammatory cell infiltration. -©---2-0--1--9--T--h--e--a--u-t-h--o--r-s-.--T--h-i-s--w---o-r-k---is---li-c-e--n--s-e--d--u--n--d-e--r--t-h-e---C--r-e--a-t-i-v-e---C--o--m--m---o-Tn--rs-o--Ap-t-t-Jr-i-bP-u-h-t-ai-or-n-m--4-R.-0-e-s-I-n,-tM-e--ra-n-r-ac-t-hi-o-2n--0a-1-l-9L--;ic--1e-8-n-(s-3-e-)-:-4--9-9 cause destruction of subsynovial cartilage and bone tissue [3]. The Hh protein family consists of sonic Hh (Shh), glioma-associated oncogene homologue (Gli1) and patched homologue 1 (Ptch). The expression of Gli and Ptch are regarded as markers of Hh pathway activity [6]
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