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Original Article | Open Access

Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma

Fengjuan Jiang1,*, Hui Liu1,*, Fengping Peng1, Zhaoyun Liu1, Kai Ding1, Jia Song1, Lijuan Li1, Jin Chen1, Qing Shao1, Siyang Yan1, Kim De Veirman2, Karin Vanderkerken2, Rong Fu1 ( )
Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels 1090, Belgium

*These authors contributed equally to this work.

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Abstract

Objective

Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease. However, the mechanism of C3a/C4a in osteoclasts MM patients remains unclear.

Methods

The formation and function of osteoclasts were analyzed after adding C3a/C4a in vitro. RNA-seq analysis was used to screen the potential pathways affecting osteoclasts, and the results were verified by Western blot, qRT-PCR, and pathway inhibitors.

Results

The osteoclast area per view induced by 1 μg/mL (mean ± SD: 50.828 ± 12.984%) and 10 μg/mL (53.663 ± 12.685%) of C3a was significantly increased compared to the control group (0 μg/mL) (34.635 ± 8.916%) (P＜0.001 and P＜0.001, respectively). The relative mRNA expressions of genes, OSCAR/TRAP/RANKL/cathepsin K, induced by 1 μg/mL (median: 5.041, 3.726, 1.638, and 4.752, respectively) and 10 μg/mL (median: 5.140, 3.702, 2.250, and 5.172, respectively) of C3a was significantly increased compared to the control group (median: 3.137, 2.004, 0.573, and 2.257, respectively) (1 μg/mL P = 0.001, P = 0.003, P＜0.001, and P = 0.008, respectively; 10 μg/mL: P＜0.001, P = 0.019, P＜0.001, and P = 0.002, respectively). The absorption areas of the osteoclast resorption pits per view induced by 1 μg/mL (mean ± SD: 51.464 ± 11.983%) and 10 μg/mL (50.219 ± 12.067%) of C3a was also significantly increased (33.845 ± 8.331%) (P＜0.001 and P＜0.001, respectively) compared to the control. There was no difference between the C4a and control groups. RNA-seq analysis showed that C3a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase (PI3K) signaling pathway. The relative expressions of PIK3CA/phosphoinositide dependent kinase-1 (PDK1)/serum and glucocorticoid inducible protein kinases (SGK3) genes and PI3K/PDK1/p-SGK3 protein in the C3a group were significantly higher than in the control group. The activation role of C3a in osteoclasts of MM patients was reduced by the SGK inhibitor (EMD638683).

Conclusions

C3a activated osteoclasts by regulating the PI3K/PDK1/SGK3 pathways in MM patients, which was reduced using a SGK inhibitor. Overall, our results identified potential therapeutic targets and strategies for MBD patients.

Keywords

Multiple myelomaosteoclastscomplement C3aPI3K/PDK1/SGK3 pathwaysSGK inhibitor

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 18 Issue 3,
August 2021
Pages 721-733
DOI: 10.20892/j.issn.2095-3941.2020.0430
Cite this article:
Jiang F, Liu H, Peng F, et al. Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma. Cancer Biology & Medicine, 2021, 18(3): 721-733. https://doi.org/10.20892/j.issn.2095-3941.2020.0430

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Received: 26 July 2020
Accepted: 27 November 2020
Published: 01 August 2021
©2021 Cancer Biology & Medicine.

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