Mechanisms of Nrf2 suppression and Camkk1 upregulation in Echinococcus granulosus-induced bone loss.

Abstract

Osteoclast differentiation is essential for maintaining bone metabolism, and its dysregulation, particularly in the context of Echinococcus granulosus (CE) infection, can lead to severe bone loss. This study explores a novel mechanism by which CE protoscolices (PSC) drive osteoclast differentiation through the inhibition of Nrf2, followed by the upregulation of Camkk1. Transcriptome sequencing revealed a significant down-regulation of Nrf2 in cells treated with PSC. This was confirmed by Western blot and Q-PCR assays showing reduced Nrf2 protein and gene levels. In vivo studies with Nrf2 knockout mice demonstrated that the absence of Nrf2 exacerbates bone loss induced by PSC in both the spine and lower limbs, as observed through Micro-CT imaging and TRAP staining.Further investigations identified Camkk1 as a key downstream target of Nrf2. Using high-throughput sequencing and CO-IP experiments, we established that Nrf2 directly interacts with and regulates Camkk1. Functional assays indicated that PSC-induced upregulation of Camkk1 is significantly enhanced by Nrf2 knockdown, while silencing Camkk1 alone inhibits osteoclast differentiation.The therapeutic potential of this pathway was evaluated by screening small molecule inhibitors of Camkk1, with Crenolani emerging as a potent compound. In vivo administration of Crenolani in PSC-treated mice significantly alleviated bone loss in a dose-dependent manner.These findings elucidate a crucial molecular mechanism in osteoclast differentiation driven by CE infection and propose a promising therapeutic strategy for combating CE-induced bone destruction. This study advances our understanding of bone.