Atlanta VA Medical Center, Decatur, GA.
Division of Endocrinology and Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA.
Blood Adv. 2019 Feb 12;3(3):288-300. doi: 10.1182/bloodadvances.2018027557.
Hemophilia A (HA), a rare X-linked recessive genetic disorder caused by insufficient blood clotting factor VIII, leaves affected individuals susceptible to spontaneous and traumatic hemorrhage. Although males generally exhibit severe symptoms, due to variable X inactivation, females can also be severely impacted. Osteoporosis is a disease of the skeleton predisposing patients to fragility fracture, a cause of significant morbidity and mortality and a common comorbidity in HA. Because the causes of osteoporosis in HA are unclear and in humans confounded by other traditional risk factors for bone loss, in this study, we phenotyped the skeletons of total knockout ( ) mice, an animal model of severe HA. We found that trabecular bone accretion in the axial and appendicular skeletons of male mice lagged significantly between 2 and 6 months of age, with more modest cortical bone decline. By contrast, in female mice, diminished bone accretion was mostly limited to the cortical compartment. Interestingly, bone loss was associated with a decline in bone formation in male mice but increased bone resorption in female mice, a possible result of sex steroid insufficiency. In conclusion, our studies reveal a sexual dimorphism in the mechanism driving bone loss in male and female mice, preventing attainment of peak bone mass and strength. If validated in humans, therapies aimed at promoting bone formation in males but suppressing bone resorption in females may be indicated to facilitate attainment of peak mass in children with HA to reduce the risk for fracture later in life.
血友病 A (HA) 是一种罕见的 X 连锁隐性遗传疾病，由凝血因子 VIII 不足引起，使受影响的个体容易发生自发性和创伤性出血。尽管男性通常表现出严重的症状，但由于 X 染色体失活的可变性，女性也可能受到严重影响。骨质疏松症是一种骨骼疾病，使患者易发生脆性骨折，这是发病率和死亡率高的原因，也是 HA 的常见合并症。由于 HA 中骨质疏松症的原因尚不清楚，并且在人类中由于其他传统的骨质流失危险因素而变得复杂，因此在这项研究中，我们对 基因敲除 ( ) 小鼠的骨骼进行了表型分析，这是一种严重 HA 的动物模型。我们发现，雄性 小鼠的轴向和附肢骨骼的小梁骨增生在 2 至 6 个月龄之间明显滞后，皮质骨下降更为温和。相比之下，在雌性小鼠中，骨增生的减少主要局限于皮质区。有趣的是，骨丢失与雄性小鼠的骨形成下降有关，但与雌性小鼠的骨吸收增加有关，这可能是由于性激素不足的结果。总之，我们的研究揭示了男性和女性 小鼠中导致骨丢失的机制存在性别二态性，阻止了峰值骨量和强度的获得。如果在人类中得到验证，针对男性促进骨形成但抑制女性骨吸收的治疗方法可能表明，为了降低 HA 患儿日后发生骨折的风险，应促进儿童获得峰值骨量。
