Abstract
Female sex is increasingly associated with a loss of bone mass during aging and an increased risk of developing nonunion fractures. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation in human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global transcriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrated craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects.
Highlights
Sexual dimorphisms are increasingly noticed to account for the severity of human disease phenotypes [1,2]
No closures of the critical-size defects were observable in controls via micro-computed tomography, we observed a significantly reduced bone mineral density (BMD) in female rats compared to male ones (Figure 1A)
A significantly decreased bone volume (BV) and BMD was further observable in female animals compared to their male counterparts after transplantation of collagen type I fibers (Figure 1B) or Spongostan (Figure 1C)
Summary
Sexual dimorphisms are increasingly noticed to account for the severity of human disease phenotypes [1,2]. Meszaros and colleagues reported a significantly increased regeneration of cranial bone defects in castrated or non-operated male mice compared to non-operated or ovariectomized female animals, suggesting the additional presence of non-hormonal mechanisms guiding sexual dimorphic bone regeneration rates [14]. In this line, increasing evidence suggests that stem cell-intrinsic mechanisms account for sex-specific differences in bone recovery and the occurrence of bone disorders (reviewed in [4]). The molecular mechanisms of the observed sex-specific differences in the osteogenic differentiation of stem cells, in the cranial and craniofacial region, are still a matter of debate
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