Wnt4 regulates bone metabolism through IKK‐NF‐κB and ROCK signaling under occlusal traumatic periodontitis

Abstract

Background and objective: Occlusal trauma is one of the most important local contributing factors of periodontitis. It has been reported that Wnt4, a noncanonical Wnt ligand, can inhibit osteoclast formation and inflammation and promote bone formation in vivo.However, the prospects of Wnt4 application in occlusal trauma and periodontitis have not yet been described. This study aimed to investigate the function and the corresponding mechanism of Wnt4 to regulate bone metabolism in occlusal trauma and periodontitis.Material and methods: Osteogenic-induced MC3T3-E1 cells were treated with or without Porphyromonas gingivalis lipopolysaccharide (Pg. LPS) under cyclic uniaxial compressive stress. After treatment with mouse recombinant protein Wnt4 (rWnt4), the expression of osteogenic markers and activation of the IKK-NF-κB signaling pathway were evaluated in vitro. To investigate whether Wnt4 can promote osteogenesis via the ROCK signaling pathway, the expression of RhoA was evaluated in vitro.Finally, we evaluated the change in bone quantity and the activation of the IKK-NF-κB and ROCK signaling in mice with occlusal trauma and periodontitis to demonstrate the therapeutic efficacy of rWnt4 injection.Results: Stimulation of traumatic force and Pg. LPS stimulation suppressed the expression of osteoblast markers, but their expression was rescued after rWnt4 treatment in vitro. In addition, the inhibition of the ROCK signaling pathway induced by force loading was reversed when rWnt4 was applied in vitro. Micro-CT, H&E, and TRAP staining of the mandibles showed increased bone loss in the occlusal trauma-aggravated periodontitis group, whereas it was rescued after rWnt4 injection. The expression levels of IκBα and p65 were upregulated in occlusal trauma and periodontitis-bearing mice, whereas the expression levels of Runx2 and RhoA were downregulated. After rWnt4 injection, remarkably upregulation of Runx2 and RhoA expression was observed in occlusal trauma and periodontitis-bearing mice. Conclusion:Wnt4 not only inhibits IKK-NF-κB signaling but also activates ROCK signaling to inhibit osteoclast formation and promote bone regeneration in occlusal trauma and periodontitis-bearing mice.

Mechanisms of mechanical force aggravating periodontitis: A review

“…In animal models, alveolar bone loss also improved after rWnt4 treatment. The potential mechanism can be explained as follows: Wnt4 inhibits IKK‐NF‐κB signaling and triggers ROCK signaling, thus suppressing osteoclast formation and promoting bone regeneration in patients diagnosed with periodontitis and occlusal trauma (Xu et al, 2022).…”

“…Occlusal trauma is defined as excessive occlusal force exerted on the teeth. Dental and periodontal tissue can be damaged as a result of the traumatic force exceeding the regenerative capacity of periodontal tissues (Xu et al, 2022). Animal models have demonstrated that occlusal trauma can also aggravate periodontitis (Wei et al, 2021).…”

ZEB1 interferes with human periodontal ligament stem cell proliferation and differentiation

“…Therefore, ROCK1 mediated the regulatory role of ZEB1 in hP-DLSCs in response to LPS. It has been reported that ROCK signaling is implicated in bone metabolism, which affects the proliferation and migration of hPDLSCs, and regulates mineralization in the periodontium (Andras et al, 2022;Wang et al, 2017;Xu et al, 2022).…”

“…Therefore, ROCK1 mediated the regulatory role of ZEB1 in hPDLSCs in response to LPS. It has been reported that ROCK signaling is implicated in bone metabolism, which affects the proliferation and migration of hPDLSCs, and regulates mineralization in the periodontium (Andras et al, 2022; Wang et al, 2017; Xu et al, 2022). Accumulating evidence has demonstrated that AMPK mediates bone loss and affects the progression of periodontitis in rats with periodontitis (Araújo et al, 2017; Díaz et al, 2020; Tamaki et al, 2014).…”

Sex-specific nociceptor modulation of the apical periodontitis transcriptome

“…After 14 days of infection, nociceptor-ablated females exhibited greater levels of Wnt7b and Wnt4, whereas cre-control females expressed more significant levels of Dkk1. There is growing evidence that both Wnt7b and Wnt4 promote the differentiation of stem cells within dental tissues, and Wnt4 has also been shown to inhibit osteoclast formation (Lv et al, 2018;Chen et al, 2019;Xu et al, 2022). Conversely, Dkk1 is a secreted inhibitor of Wnt signaling and known to play a role in negative feedback within this pathway (Cao et al, 2015).…”