Department of Natural Sciences, University of Michigan-Dearborn, 4901 Evergreen Rd, Dearborn, MI 48128, USA.
School of Dentistry, University of Michigan-Ann Arbor, 1011 N University Avenue, Ann Arbor, MI 48103, USA.
Int J Mol Sci. 2021 Jan 24;22(3):1140. doi: 10.3390/ijms22031140.
Tissue nonspecific alkaline phosphatase (TNAP/) is associated with cell stemness; however, the function of TNAP in mesenchymal progenitor cells remains largely unknown. In this study, we aimed to establish an essential role for TNAP in bone and muscle progenitor cells. We investigated the impact of TNAP deficiency on bone formation, mineralization, and differentiation of bone marrow stromal cells. We also pursued studies of proliferation, mitochondrial function and ATP levels in TNAP deficient bone and muscle progenitor cells. We find that TNAP deficiency decreases trabecular bone volume fraction and trabeculation in addition to decreased mineralization. We also find that mice (global TNAP knockout mice) exhibit muscle and motor coordination deficiencies similar to those found in individuals with hypophosphatasia (TNAP deficiency). Subsequent studies demonstrate diminished proliferation, with mitochondrial hyperfunction and increased ATP levels in TNAP deficient bone and muscle progenitor cells, plus intracellular expression of TNAP in TNAP+ cranial osteoprogenitors, bone marrow stromal cells, and skeletal muscle progenitor cells. Together, our results indicate that TNAP functions inside bone and muscle progenitor cells to influence mitochondrial respiration and ATP production. Future studies are required to establish mechanisms by which TNAP influences mitochondrial function and determine if modulation of TNAP can alter mitochondrial respiration in vivo.
组织非特异性碱性磷酸酶（TNAP）与细胞干性有关；然而，TNAP 在间充质祖细胞中的功能在很大程度上仍然未知。在这项研究中，我们旨在确定 TNAP 在骨和肌肉祖细胞中的重要作用。我们研究了 TNAP 缺乏对骨髓基质细胞的成骨、矿化和分化的影响。我们还研究了 TNAP 缺陷的骨和肌肉祖细胞的增殖、线粒体功能和 ATP 水平。我们发现 TNAP 缺乏会降低小梁骨体积分数和小梁化，同时减少矿化。我们还发现，（全局 TNAP 敲除小鼠）表现出类似于低磷酸酶症（TNAP 缺乏）患者的肌肉和运动协调缺陷。随后的研究表明，TNAP 缺陷的骨和肌肉祖细胞的增殖减少，线粒体功能亢进，ATP 水平升高，同时 TNAP 在 TNAP+颅骨祖细胞、骨髓基质细胞和骨骼肌祖细胞中表达。总之，我们的结果表明，TNAP 在骨和肌肉祖细胞内发挥作用，影响线粒体呼吸和 ATP 产生。需要进一步的研究来确定 TNAP 影响线粒体功能的机制，并确定是否可以调节 TNAP 来改变体内的线粒体呼吸。
