Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?
Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?
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DOI：
10.1007/s11999-015-4268-z
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发表时间：
2015-08-01
影响因子：
4.2
通讯作者：
Raggio, Cathleen L.
中科院分区：
文献类型：
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作者：
Boskey, Adele L.;Marino, Josephine;Raggio, Cathleen L.
成骨不全症是一种以骨骼脆弱和畸形为特征的遗传性疾病。关于成人成骨不全症的治疗方案存在广泛的争论。抗吸收治疗可减少生长中的oim/oim小鼠的骨折数量，这是一种可重复模仿人类中度至重度OI的动物模型。长期使用抗吸收药物治疗具有类似症状的老年成骨不全患者（中度至重度成骨不全）的效果迄今尚不清楚。傅里叶变换红外（FTIR）成像技术可以生成骨薄片中化学成分的空间变化图，用于解决以下问题：(1)在6.5个月大时，oim/oim小鼠在成分特性上是否表现出性别依赖性；(2)人类成骨不全患者对抗吸收药物治疗是否存在性别依赖性反应；(3)治疗后，oim/oim小鼠的任何组成参数是否被纠正为野生型（WT）值？FTIR成像数据收集自每种性别、每种基因型、每种治疗的4 - 5只小鼠的股骨。治疗为24周生理盐水、阿仑膦酸盐或RANK-Fc；12周生理盐水+ 12周RANK-Fc和12周阿仑膦酸盐+ RANK-Fc。在皮质骨和松质骨中测量的FTIR成像组成参数包括矿物-基质比、碳酸盐-矿物比、晶体大小/完美度、酸磷酸盐取代、胶原成熟度及其各自的分布（异质性）。由于样本量较小，采用非参数统计（Mann-Whitney U-和Kruskal-Wallis检验，并进行Bonferroni校正），分别按性别和基因型比较不同基因型的雄性和雌性小鼠的盐处理和治疗效果。p < 0.05为差异有统计学意义。在6.5个月时，与WT相比，经盐水处理的雄性皮质油/油骨的矿物-基质比增加（p = 0.016），酸性磷酸盐取代量增加（p = 0.032），碳酸盐-矿物比降低（p = 0.016）。与雄性WT相比，雄性油/油骨的松质骨的矿物-基质比也增加（p = 0.016）。雌性油/油小鼠骨骼组成的所有皮质和松质骨参数与WT相当（p >.05）。只有雌性WT小鼠对处理表现出平均组成特性的反应，与盐水处理小鼠相比，在RANK-Fc处理后松质骨中矿物质与基质的比例增加（p = 0.036）。除了生理盐水+ RANK-Fc外，男性oim/oim对所有长期治疗的反应都增加了矿物质-基质皮质骨和松质骨的异质性（p < 0.04）；随着ALN + RANK-Fc的增加，女性骨皮质矿物与基质的异质性增加，所有处理均增加了松质女性骨皮质矿物与基质的异质性（p < 0.04）。oim/oim和WT小鼠在生理盐水治疗中表现出性别依赖的成分差异，对长期使用抗吸收药物治疗几乎没有反应。雌性WT小鼠似乎反应更灵敏；雄性oim/oim小鼠的成分异质性变化更大。这些药物引起的骨成分变化可能有助于改善oim/oim小鼠的骨质量，因为已知这些治疗可以减少骨折发生率。中重度成骨不全患者长期治疗的最佳药物治疗尚不清楚。基于小鼠骨成分的变化，抗骨吸收治疗对于成骨不全的持续治疗是有用的。据报道，成人成骨不全患者的骨折发生率存在性别二型性，但迄今为止，还没有人报道对药物干预的反应存在差异。这项研究表明，这样的调查是有必要的。
Osteogenesis imperfecta (OI) is a genetic disease characterized by skeletal fragility and deformity. There is extensive debate regarding treatment options in adults with OI. Antiresorptive treatment reduces the number of fractures in growing oim/oim mice, an animal model that reproducibly mimics the moderate-to-severe form of OI in humans. Effects of long-term treatments with antiresorptive agents, considered for treatment of older patients with OI with similar presentation (moderate-to-severe OI) are, to date, unknown.Fourier transform infrared (FTIR) imaging, which produces a map of the spatial variation in chemical composition in thin sections of bone, was used to address the following questions: (1) do oim/oim mice show a sex dependence in compositional properties at 6.5 months of age; (2) is there a sex-dependent response to treatment with antiresorptive agents used in the treatment of OI in humans; and (3) are any compositional parameters in oim/oim mice corrected to wild-type (WT) values after treatment?FTIR imaging data were collected from femurs from four to five mice per sex per genotype per treatment. Treatments were 24 weeks of saline, alendronate, or RANK-Fc; and 12 weeks of saline + 12 weeks RANK-Fc and 12 weeks of alendronate + RANK-Fc. FTIR imaging compositional parameters measured in cortical and cancellous bones were mineral-to-matrix ratio, carbonate-to-mineral ratio, crystal size/perfection, acid phosphate substitution, collagen maturity, and their respective distributions (heterogeneities). Because of the small sample size, nonparametric statistics (Mann-Whitney U- and Kruskal-Wallis tests with Bonferroni correction) were used to compare saline-treated male and female mice of different genotypes and treatment effects by sex and genotype, respectively. Statistical significance was defined as p < 0.05.At 6.5 months, saline-treated male cortical oim/oim bone had increased mineral-to-matrix ratio (p = 0.016), increased acid phosphate substitution (p = 0.032), and decreased carbonate-to-mineral ratio (p = 0.016) relative to WT. Cancellous bone in male oim/oim also had increased mineral-to-matrix ratio (p = 0.016) relative to male WT. Female oim/oim mouse bone composition for all cortical and cancellous bone parameters was comparable to WT (p > 0.05). Only the female WT mice showed a response of mean compositional properties to treatment, increasing mineral-to-matrix after RANK-Fc treatment in cancellous bone (p = 0.036) compared with saline-treated mice. Male oim/oim increased mineral-to-matrix cortical and cancellous bone heterogeneity in response to all long-term treatments except for saline + RANK-Fc (p < 0.04); female oim/oim cortical mineral-to-matrix bone heterogeneity increased with ALN + RANK-Fc and all treatments increased cancellous female oim/oim bone acid phosphate substitution heterogeneity (p < 0.04).Both oim/oim and WT mice, which demonstrate sex-dependent differences in composition with saline treatment, showed few responses to long-term treatment with antiresorptive agents. Female WT mice appeared to be more responsive; male oim/oim mice showed more changes in compositional heterogeneity. Changes in bone composition caused by these agents may contribute to improved bone quality in oim/oim mice, because the treatments are known to reduce fracture incidence.The optimal drug therapy for long-term treatment of patients with moderate-to-severe OI is unknown. Based on bone compositional changes in mice, antiresorptive treatments are useful for continued treatment in OI. There is a reported sexual dimorphism in fracture incidence in adults with OI, but to date, no one has reported differences in response to pharmaceutical intervention. This study suggests that such an investigation is warranted.