TY - JOUR
T1 - Thrombospondin 2 promotes il-6 production in osteoarthritis synovial fibroblasts via the pi3k/ akt/nf-κb pathway
AU - Hou, Chun Han
AU - Tang, Chih Hsin
AU - Chen, Po Chun
AU - Liu, Ju Fang
N1 - Funding Information:
This work was supported by grants from Taiwan’s Ministry of Science and Technology (MOST-108-2314-B-002-211-MY3, MOST-107-2314-B-341-003, MOST106-2314-B-341-001-MY3) and the Shin-Kong Wu Ho-Su Memorial Hospital (SKH-8302-106-0401). We would like to thank Iona J. MacDonald in China Medical University for her English language revision of this manuscript. We thank the staff of the Eighth Core Lab, Department of Medical Research, National Taiwan University Hospital for technical support during the study.
Publisher Copyright:
© 2021 Hou et al.
PY - 2021
Y1 - 2021
N2 - Background: It is known that osteoarthritis (OA) pathogenesis involves inflammation that drives pathologic changes and that the matricellular protein, thrombospondin-2 (TSP2), is involved in angiogenesis, carcinogenesis, and inflammation. However, how TSP2 contributes to OA inflammatory processes is unclear. Objective: The aim of current study was to elucidate whether TSP2 could promote interleukin-6 (IL-6), a pro-inflammatory cytokine, expression in osteoarthritis synovial fibroblasts (OASFs). Methods: The synovial fibroblasts isolated from osteoarthritis and healthy donors were incubated with recombinant TSP2 to evaluate its effect in OA pathogenesis. The SFs were incubated with recombinant TSP2, followed by determining the IL-6 expression by qPCR and Western blot. After SFs were incubated with TSP2 for different time interval, the Western blot was performed to investigate the activation of signal pathway. The different strategies including neutralizing antibodies, siRNAs, and chemical inhibitors were used to discover the signal transduction in response to TSP2 incubation in OASFs. To evaluate the therapeutic potential of TSP2 in osteoarthritis, the anterior cruciate ligament transection (ACLT) in SD rats was performed in the presence or absence of TSP neutralizing antibody treatment. Results: Our investigations have revealed that TSP2 promoted IL-6 expression in OASFs in a dose-dependent manner, especially in 30 and 100 ng/mL concentration (p < 0.05). Using different strategies including neutralizing antibodies, siRNAs, and chemical inhibitors, all of which attenuated signal pathway components in OASFs, we found evidence for the involvement of integrin αvβ3, PI3K, Akt, and NF-κB in TSP2-mediated upregulation of IL-6 (p < 0.05). Finally, in the result of rat ACLT surgical model, we found that TSP2 neutralizing antibody had protective effects in cartilage destruction during OA progression. Conclusion: Thrombospondin-2 palys an important role in osteoarthritis pathogenesis and provides an opportunity to deal with osteoarthritis.
AB - Background: It is known that osteoarthritis (OA) pathogenesis involves inflammation that drives pathologic changes and that the matricellular protein, thrombospondin-2 (TSP2), is involved in angiogenesis, carcinogenesis, and inflammation. However, how TSP2 contributes to OA inflammatory processes is unclear. Objective: The aim of current study was to elucidate whether TSP2 could promote interleukin-6 (IL-6), a pro-inflammatory cytokine, expression in osteoarthritis synovial fibroblasts (OASFs). Methods: The synovial fibroblasts isolated from osteoarthritis and healthy donors were incubated with recombinant TSP2 to evaluate its effect in OA pathogenesis. The SFs were incubated with recombinant TSP2, followed by determining the IL-6 expression by qPCR and Western blot. After SFs were incubated with TSP2 for different time interval, the Western blot was performed to investigate the activation of signal pathway. The different strategies including neutralizing antibodies, siRNAs, and chemical inhibitors were used to discover the signal transduction in response to TSP2 incubation in OASFs. To evaluate the therapeutic potential of TSP2 in osteoarthritis, the anterior cruciate ligament transection (ACLT) in SD rats was performed in the presence or absence of TSP neutralizing antibody treatment. Results: Our investigations have revealed that TSP2 promoted IL-6 expression in OASFs in a dose-dependent manner, especially in 30 and 100 ng/mL concentration (p < 0.05). Using different strategies including neutralizing antibodies, siRNAs, and chemical inhibitors, all of which attenuated signal pathway components in OASFs, we found evidence for the involvement of integrin αvβ3, PI3K, Akt, and NF-κB in TSP2-mediated upregulation of IL-6 (p < 0.05). Finally, in the result of rat ACLT surgical model, we found that TSP2 neutralizing antibody had protective effects in cartilage destruction during OA progression. Conclusion: Thrombospondin-2 palys an important role in osteoarthritis pathogenesis and provides an opportunity to deal with osteoarthritis.
KW - IL-6
KW - Integrin αβ
KW - Osteoarthritis
KW - TSP2
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U2 - 10.2147/JIR.S314747
DO - 10.2147/JIR.S314747
M3 - Article
AN - SCOPUS:85119346740
SN - 1178-7031
VL - 14
SP - 5955
EP - 5967
JO - Journal of Inflammation Research
JF - Journal of Inflammation Research
ER -