Abstract
Osteoarthritis (OA) is a chronic joint disorder that causes cartilage degradation and subchondral bone abnormalities. Nangibotide, also known as LR12, is a dodecapeptide with considerable anti-inflammatory properties, but its significance in OA is uncertain. The aim of the study was to determine whether nangibotide could attenuate the progression of OA, and elucidate the underlying mechanism. In vitro experiments showed that nangibotide strongly inhibited TNF-α-induced osteogenic reduction, significantly enhanced osteoblast proliferation and prevented apoptosis in MC3T3-E1 cells. Male C57BL/6 J mice aged 2 months were randomly allocated to three groups: sham, ACLT, and ACLT with nangibotide therapy. Nangibotide suppressed ACLT-induced cartilage degradation and MMP-13 expression. MicroCT analysis revealed that nangibotide attenuated in vivo subchondral bone loss induced by ACLT. Histomorphometry results showed that nangibotide attenuated ACLT-induced osteoblast inhibition; TUNEL assays and immunohistochemical staining of cleaved-caspase3 further confirmed the in vivo anti-apoptotic effect of nangibotide on osteoblasts. Furthermore, we found that nangibotide exerted protective effects by suppressing TGF-β signaling mediated by Smad2/3 to restore coupled bone remodeling in the subchondral bone. In conclusion, the findings suggest that nangibotide might exert a protective effect on the bone-cartilage unit and maybe an alternative treatment option for OA.
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All data included in this study are available from the corresponding author on reasonable request.
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Funding
This work was supported by the National Natural Science Foundation of China [grant numbers: 82172411, 81871795], Shanghai Municipal Health and Family Planning Commission [grant number: SHDC12017121] and Songjiang District Science and Technology Project [grant number: 18sjkjgg18].
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YZ and YX contributed to the experimental work and prepared the first draft of the paper. SX and LZ were responsible for the acquisition of the data. HL, CW and HC were responsible for the statistical analysis of the data. WS and JM designed the study and they are guarantors. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.
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The study protocol has been approved by the Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (#2020AWS0008, approved on March 23, 2020). All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals and approved by the Ethical Committee of the Shanghai General Hospital.
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Zhong, Y., Xu, Y., Xue, S. et al. Nangibotide attenuates osteoarthritis by inhibiting osteoblast apoptosis and TGF-β activity in subchondral bone. Inflammopharmacol 30, 1107–1117 (2022). https://doi.org/10.1007/s10787-022-00984-2
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DOI: https://doi.org/10.1007/s10787-022-00984-2