Ano5<sup>Cys360Tyr</sup> mutation leads to bone dysfunction of gnathodiaphyseal dysplasia <i>via</i> disturbing Akt signaling.
basic_science · Level V
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- Record sourced from PubMed, PMID 39866532.
- Also identified by DOI 10.1016/j.bonr.2025.101825 and PMC identifier 11763220.
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Abstract
Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease characterized by osteosclerosis of the tubular bones and cemento-osseous lesions of the mandibles. <i>Anoctamin 5</i> (<i>ANO5</i>) is the pathogenic gene, however, the specific molecular mechanism of GDD remains unclear. Herein, a knockin (<i>Ano5</i> <sup><i>KI/KI</i></sup> ) mouse model expressing the human mutation p.Cys360Tyr was used to investigate the role of Akt signaling in enhanced osteogenesis and decreased osteoclastogenesis in GDD. Bone marrow-derived macrophages (BMMs) and mouse calvarial osteoblasts (mCOBs) were isolated from homozygous <i>Ano5</i> <sup><i>KI/KI</i></sup> mice and treated with SC79, a specific Akt activator. The differentiation and F-actin ring formation of osteoclasts were examined by TRAP and phalloidin staining, respectively. Osteoblast differentiation and mineralization were examined by ALP and alizarin red staining. The expression of bone remodeling-related factors was measured by qRT-PCR. Akt activation promoted the generation of TRAP-positive multinucleated osteoclasts and the formation of actin rings in <i>Ano5</i> <sup><i>KI/KI</i></sup> BMMs cultures, accompanied by increased expression of <i>Nfatc1</i>, <i>Trap</i>, <i>Dc-stamp</i>, <i>Mmp9</i>, <i>Ctsk</i>, and <i>Atp6v0d2</i>. Additionally, <i>Ano5</i> <sup><i>Cys360Tyr</i></sup> mutation down-regulated the Akt phosphorylation level in osteoblast. ALP activity and matrix mineralization capacity in <i>Ano5</i> <sup><i>KI/KI</i></sup> osteoblast cultures were inhibited after SC79 stimulation, with reduced expression of <i>Runx2, Opn, Col1a1</i>, <i>and Ocn</i>. Akt activation by SC79 stimulation can obviously rescue abnormal increased osteogenesis and decreased osteoclastogenesis in <i>Ano5</i> <sup><i>KI/KI</i></sup> mouse model, which demonstrated that disturbed Akt signaling pathway may play a pivotal role in the pathogenesis of GDD, and an Akt activator is probable a therapeutic target for GDD.