Department of Anatomy & Cell Biology, Rush University Medical Center, Chicago, IL, USA; Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA.
Department of Anatomy & Cell Biology, Rush University Medical Center, Chicago, IL, USA; Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA.
Bone. 2022 Nov;164:116524. doi: 10.1016/j.bone.2022.116524. Epub 2022 Aug 24.
There are over one million cases of failed bone repair in the U.S. annually, resulting in substantial patient morbidity and societal costs. Multiple candidate genes affecting bone traits such as bone mineral density have been identified in human subjects and animal models using genome-wide association studies (GWAS). This approach for understanding the genetic factors affecting bone repair is impractical in human subjects but could be performed in a model organism if there is sufficient variability and heritability in the bone regeneration response. Diversity Outbred (DO) mice, which have significant genetic diversity and have been used to examine multiple intact bone traits, would be an excellent possibility. Thus, we sought to evaluate the phenotypic distribution of bone regeneration, sex effects and heritability of intramembranous bone regeneration on day 7 following femoral marrow ablation in 47 12-week old DO mice (23 males, 24 females). Compared to a previous study using 4 inbred mouse strains, we found similar levels of variability in the amount of regenerated bone (coefficient of variation of 86 % v. 88 %) with approximately the same degree of heritability (0.42 v. 0.49). There was a trend toward more bone regeneration in males than females. The amount of regenerated bone was either weakly or not correlated with bone mass at intact sites, suggesting that the genetic factors responsible for bone regeneration and intact bone phenotypes are at least partially independent. In conclusion, we demonstrate that DO mice exhibit variation and heritability of intramembranous bone regeneration that will be suitable for future GWAS.
美国每年有超过 100 万例骨修复失败的病例，导致患者发病率和社会成本大幅上升。使用全基因组关联研究（GWAS）在人类和动物模型中已经鉴定出多个影响骨密度等骨特征的候选基因。这种了解影响骨修复的遗传因素的方法在人类受试者中不切实际，但如果在骨再生反应中有足够的可变性和遗传性，就可以在模型生物中进行。具有显著遗传多样性并已用于研究多种完整骨特征的多样性杂交（DO）小鼠将是一个极好的可能性。因此，我们试图评估 47 只 12 周龄 DO 小鼠（23 只雄性，24 只雌性）在股骨骨髓消融后第 7 天的骨再生表型分布、性别效应和膜内骨再生的遗传力。与之前使用 4 个近交系小鼠品系的研究相比，我们发现再生骨量的变异性相似（变异系数为 86%比 88%），遗传力也大致相同（0.42 比 0.49）。雄性的骨再生量比雌性多，有趋势表明雄性的骨再生量比雌性多。再生骨量与完整部位的骨量之间要么弱相关，要么不相关，这表明负责骨再生和完整骨表型的遗传因素至少部分是独立的。总之，我们证明 DO 小鼠表现出膜内骨再生的变异性和遗传力，这将适合未来的 GWAS。
