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. 2024 Dec;1871(8):119850.
doi: 10.1016/j.bbamcr.2024.119850. Epub 2024 Sep 19.

Microbial chaperonin 60 inhibits osteoclast differentiation by interfering with RANK/RANKL binding and overexpression of lipocalin2

Joo-Young Cho  1 , Hee-Eun Woo  1 , Jiah Yeom  1 , Mirae An  2 , Seongho Ma  1 , Dong Joon Yim  1 , Sang-Hun Kim  1 , Young-Hee Lim  3
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Free article

Microbial chaperonin 60 inhibits osteoclast differentiation by interfering with RANK/RANKL binding and overexpression of lipocalin2

Joo-Young Cho et al. Biochim Biophys Acta Mol Cell Res. 2024 Dec.
Free article

Abstract

Osteoclasts play a crucial role in bone destruction in rheumatoid arthritis (RA). This study aimed to investigate the inhibitory effects of chaperonin 60 (CPN60), identified in the surface proteins of Propionibacterium freudenreichii MJ2, on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation, and elucidate the underlying mechanisms. Treatment with CPN60 inhibited RANKL-induced osteoclast differentiation by decreasing the expression of osteoclast differentiation-related genes and proteins. CPN60 interfered with the binding of RANKL to RANK, as elucidated using surface plasmon resonance (SPR) and immunofluorescence. In silico molecular docking analysis further supported the interference of CPN60 with the binding of RANKL and RANK. CPN60 suppressed the expression of molecules linked to the calcium-dependent pathway in RANKL-induced osteoclast differentiation at both mRNA and protein levels. Microarray analysis showed elevated expression of lipocalin 2 (Lcn2), which was closely linked to the inhibition of osteoclast differentiation in CPN60-treated RAW 264.7 cells. Inhibition of Lcn2 decreased the inhibitory effect of CPN60 on osteoclast differentiation, indicating that increased expression of Lcn2 by CPN60 contributes to the inhibition of osteoclastogenesis. In addition, CPN60 treatment alleviated arthritis symptoms in collagen-induced arthritis mice by reducing the generation of collagen-specific antibodies and inhibiting osteoclast differentiation. In conclusion, CPN60 of P. freudenreichii MJ2 interfered with RANKL-RANK binding, reduced the expression of genes and proteins related to osteoclast differentiation and upregulated Lcn2 expression, thereby inhibiting RANKL-induced osteoclast differentiation, which might contribute to ameliorate collagen-induced arthritis.

Keywords: Chaperonin 60; Collagen-induced arthritis mouse; In silico analysis; Lipocalin 2; Osteoclastogenesis; RANKL.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Young-Hee Lim reports a relationship with National Research Foundation of Korea (NRF) that includes: funding grants. Young-Hee Lim has patent #PCT/KR2023/017254 pending to Korea University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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