Dhx36 loss may accelerate BMSC and age-related bone loss by disrupting stress-granule and regulation.
Evidence
This cell and mouse mechanistic study silenced or knocked out Dhx36 in BMSCs, compared young and aged mouse bone tissue, and analyzed public single-cell RNA sequencing data after 5-fluorouracil stress.
Caveat
The evidence is preclinical and mechanistic, so Dhx36 is only a potential therapeutic target rather than a proven intervention for osteoporosis.
Simplified
of mesenchymal stem cells in bone tissue (BMSCs), the primary progenitors of osteoblasts, is a key contributor to age-related osteopenia and osteoporosis. Aged cells exhibit elevated cellular stress and abnormal accumulation of (SGs), which contain G-quadruplex (G4) structured nucleic acids and G4-binding proteins. Dhx36, a helicase that unwinds G4 structure, may play a protective role in this context. In this study, we investigated the function of Dhx36 in BMSCs and bone homeostasis by silencing Dhx36 expression in vitro and in vivo. Dhx36 deficiency increased SG formation and impaired their resolution in BMSCs. This was accompanied by reduced expression of G4-containing autophagyrelated genes and diminished autophagic activity. Loss of Dhx36 also enhanced senescence features and impaired BMSC osteogenic differentiation. Dhx36 expression was significantly lower in bone tissue and BMSCs from aged mice, compared to young mice. Moreover, 8-week-old mice with BMSC-specific Dhx36 knockout exhibited reduced bone volume and trabecular number, indicating premature bone loss. Analysis of public singlecell RNA sequencing data further showed that stress induced by 5-fluorouracil in mice suppressed Dhx36 expression in BMSCs, and downregulated genes related to ossification and osteoblast differentiation. Collectively, our findings identify Dhx36 as a regulator of BMSC aging, linking SG dynamics and to bone homeostasis, and suggest Dhx36 as a potential therapeutic target to prevent age-related bone loss. [BMB Reports 2025; 58(12): 501-510].
Key numbers
BV/TV decreased in Dhx36 knockout mice
Decrease in Bone Volume Fraction
Bone volume fraction in BMSC-specific Dhx36 knockout mice compared to controls.
Elevated p53 and p21 levels in Dhx36-deficient BMSCs
Increased Markers
Protein levels of markers in BMSCs after Dhx36 knockdown.
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