Sungsin Jo1, Eun Jeong Won2, Moon-Ju Kim2, Yu Jeong Lee2, So-Hee Jin3, Pu-Reum Park3, Ho-Chun Song4, Jahae Kim4, Yoo-Duk Choi5, Ji-Young Kim6, Seung Cheol Shim6, Sung Hoon Choi7, Ye-Soo Park8, Tae-Hwan Kim1,9, Tae-Jong Kim3. 1. Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea. 2. Department of Parasitology and Tropical Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. 3. Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. 4. Department of Nuclear Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. 5. Department of Pathology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. 6. Division of Rheumatology, Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Republic of Korea. 7. Department of Orthopedic Surgery, Hanyang University Hospital, Seoul, Republic of Korea. 8. Department of Orthopedic Surgery, Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea. 9. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
Abstract
OBJECTIVE: AS is a rheumatic disease characterized by chronic inflammation and bony ankylosis. This study was to evaluate whether a signal transducer and activator of transcription 3 phosphorylation inhibitor (stat3-p Inh) could treat both chronic inflammation and bone formation in AS. METHODS: Primary AS osteoprogenitor cells and spinal entheseal cells were examined for osteogenic differentiation. SF mononuclear cells (SFMCs) and lamina propria mononuclear cells (LPMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analysed using flow cytometry and ELISA. Female SKG mice were treated with stat3-p Inh, IL-17A blocker or vehicle. Inflammation and new bone formation were evaluated using immunohistochemistry, PET and micro-CT. RESULTS: In the SKG mouse model, stat3-p Inh significantly suppressed arthritis, enthesitis, spondylitis and ileitis. In experiments culturing SFMCs and LPMCs, the frequencies of IFN-γ-, IL-17A- and TNF-α-producing cells were significantly decreased after stat3-p Inh treatment. When comparing current treatments for AS, stat3-p Inh showed a comparable suppression effect on osteogenesis to Janus kinase inhibitor or IL-17A blocker in AS-osteoprogenitor cells. Stat3-p Inh suppressed differentiation and mineralization of AS-osteoprogenitor cells and entheseal cells toward osteoblasts. Micro-CT analysis of hind paws revealed less new bone formation in stat3-p Inh-treated mice than vehicle-treated mice (P = 0.005). Hind paw and spinal new bone formation were similar between stat3-p Inh- and anti-IL-17A-treated SKG mice (P = 0.874 and P = 0.117, respectively). CONCLUSION: Stat-3p inhibition is a promising treatment for both inflammation and new bone formation in AS.
OBJECTIVE: AS is a rheumatic disease characterized by chronic inflammation and bony ankylosis. This study was to evaluate whether a signal transducer and activator of transcription 3 phosphorylation inhibitor (stat3-p Inh) could treat both chronic inflammation and bone formation in AS. METHODS: Primary AS osteoprogenitor cells and spinal entheseal cells were examined for osteogenic differentiation. SF mononuclear cells (SFMCs) and lamina propria mononuclear cells (LPMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analysed using flow cytometry and ELISA. Female SKG mice were treated with stat3-p Inh, IL-17A blocker or vehicle. Inflammation and new bone formation were evaluated using immunohistochemistry, PET and micro-CT. RESULTS: In the SKG mouse model, stat3-p Inh significantly suppressed arthritis, enthesitis, spondylitis and ileitis. In experiments culturing SFMCs and LPMCs, the frequencies of IFN-γ-, IL-17A- and TNF-α-producing cells were significantly decreased after stat3-p Inh treatment. When comparing current treatments for AS, stat3-p Inh showed a comparable suppression effect on osteogenesis to Janus kinase inhibitor or IL-17A blocker in AS-osteoprogenitor cells. Stat3-p Inh suppressed differentiation and mineralization of AS-osteoprogenitor cells and entheseal cells toward osteoblasts. Micro-CT analysis of hind paws revealed less new bone formation in stat3-p Inh-treated mice than vehicle-treated mice (P = 0.005). Hind paw and spinal new bone formation were similar between stat3-p Inh- and anti-IL-17A-treated SKG mice (P = 0.874 and P = 0.117, respectively). CONCLUSION:Stat-3p inhibition is a promising treatment for both inflammation and new bone formation in AS.
Authors: Hong Ki Min; JeongWon Choi; Seon-Yeong Lee; A Ram Lee; Byung-Moo Min; Mi-La Cho; Sung-Hwan Park Journal: PLoS One Date: 2022-01-05 Impact factor: 3.240