Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15224, United States of America.
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15224, United States of America.
Mol Genet Metab. 2021 Mar;132(3):173-179. doi: 10.1016/j.ymgme.2021.01.014. Epub 2021 Feb 11.
Osteopenia occurs in a subset of phenylalanine hydroxylase (PAH) deficient phenylketonuria (PKU) patients. While osteopenia is not fully penetrant in patients, the Pah classical PKU mouse is universally osteopenic, making it an ideal model of the phenotype. Pah Phe management, with a Phe-fee amino acid defined diet, does not improve bone density as histomorphometry metrics remain indistinguishable from untreated animals. Previously, we demonstrated Pah mesenchymal stem cells (MSCs) display impaired osteoblast differentiation. Oxidative stress is recognized in PKU patients and PKU animal models. Pah MSCs experience oxidative stress determined by intracellular superoxide over-representation. The deleterious impact of oxidative stress on mitochondria is recognized. Oximetry applied to Pah MSCs identified mitochondrial stress by increased basal respiration with concurrently reduced maximal respiration and respiratory reserve. Proton leak secondary to mitochondrial complex 1 dysfunction is a recognized superoxide source. Respirometry applied to Pah MSCs, in the course of osteoblast differentiation, identified a partial complex 1 deficit. Pah MSCs treated with the antioxidant resveratrol demonstrated increased mitochondrial mass by MitoTracker green labeling. In hyperphenylalaninemic conditions, resveratrol increased in situ alkaline phosphatase activity suggesting partial recovery of Pah MSCs osteoblast differentiation. Up-regulation of oxidative energy production is required for osteoblasts differentiation. Our data suggests impaired Pah MSC developmental competence involves an energy deficit. We posit energy support and oxidative stress reduction will enable Pah MSC differentiation in the osteoblast lineage to subsequently increase bone density.
骨质疏松症发生在一部分苯丙氨酸羟化酶（PAH）缺乏的苯丙酮尿症（PKU）患者中。虽然骨质疏松症在患者中不完全表现，但 Pah 经典 PKU 小鼠普遍存在骨质疏松症，使其成为该表型的理想模型。用不含苯丙氨酸的氨基酸定义饮食进行 Pah phe 管理，并不能改善骨密度，因为组织形态计量学指标与未治疗的动物没有区别。以前，我们证明了 Pah 间充质干细胞（MSCs）的成骨细胞分化受损。氧化应激在 PKU 患者和 PKU 动物模型中得到证实。Pah MSCs 经历由细胞内超氧化物过度表达引起的氧化应激。线粒体受到氧化应激的有害影响已被认识到。氧饱和度测定法应用于 Pah MSCs，通过增加基础呼吸来识别线粒体应激，同时降低最大呼吸和呼吸储备。线粒体复合物 1 功能障碍引起的质子泄漏是公认的超氧化物源。呼吸测定法应用于成骨细胞分化过程中的 Pah MSCs，发现存在部分复合物 1 缺陷。用抗氧化剂白藜芦醇处理 Pah MSCs 后，通过 MitoTracker green 标记显示线粒体质量增加。在高苯丙氨酸血症条件下，白藜芦醇增加了原位碱性磷酸酶活性，表明 Pah MSCs 成骨细胞分化部分恢复。成骨细胞分化需要上调氧化能量产生。我们的数据表明，Pah MSC 发育能力受损涉及能量不足。我们假设能量支持和氧化应激减少将使 Pah MSC 在成骨细胞谱系中分化，随后增加骨密度。
