Tissue Nonspecific Alkaline Phosphatase Function in Bone and Muscle Progenitor Cells: Control of Mitochondrial Respiration and ATP Production

Abstract

Tissue nonspecific alkaline phosphatase (TNAP/Alpl) 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 Alpl−/− 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.

Hypophosphatasia: A Unique Disorder of Bone Mineralization

“…Recent studies have shown that TNSALP may have a regulatory role in bone and muscle progenitor cells influencing musculoskeletal health. Thus, low levels of this enzyme have been associated with muscle weakness and diminished motor coordination [ 51 ]. Additionally, it has been revealed that TNSALP can modulate mitochondrial function and ATP levels, and defects in it can be associated with mitochondrial dysfunction, cell respiration, and increased reactive oxygen species, leading to metabolic disturbances in this population [ 51 ].…”

“…Thus, low levels of this enzyme have been associated with muscle weakness and diminished motor coordination [ 51 ]. Additionally, it has been revealed that TNSALP can modulate mitochondrial function and ATP levels, and defects in it can be associated with mitochondrial dysfunction, cell respiration, and increased reactive oxygen species, leading to metabolic disturbances in this population [ 51 ]. The different manifestations can be classified from the most severe to the mildest forms in perinatal lethal hypophosphatasia, infantile hypophosphatasia, childhood-onset hypophosphatasia, adult hypophosphatasia, odontohypophosphatasia, and benign perinatal hypophosphatasia [ 8 , 21 , 26 ].…”

TNAP: A New Multitask Enzyme in Energy Metabolism

“…Published data however report data difficult to reconcile, maybe relying on the different maturation stage of cells used in these studies. It was for instance shown that bone marrow stromal cells from Alpl −/− or Alpl +/− mice or from patients with hypophosphatasia generate more adipocytes than bone marrow stromal cells from corresponding controls [ 92 , 93 , 94 ], suggesting that TNAP prevents MSC commitment toward adipocytes. On the other hand, Esteve et al, reported that TNAP was particularly expressed in a subpopulation of beige adipocyte progenitors, where its chemical or molecular inhibition reduced the levels of markers associated with adipocyte differentiation (PPARγ2, ChREBP, UCP1, LPL), and decreased TG accumulation [ 95 ].…”

“…To our knowledge, TNAP lacks classical mitochondrial addressing signals. Interestingly, an article published in this issue reports that TNAP is also likely associated with mitochondria in bone and muscle progenitor cells [ 94 ]. In these cells, TNAP inhibition increased mitochondrial respiration and ATP production [ 94 ], providing molecular evidence to understand why TNAP-deficient mice, sheep and humans have mitochondria with disorganized cristae and/or reduced muscle strength [ 15 , 94 , 103 ].…”

“…Interestingly, an article published in this issue reports that TNAP is also likely associated with mitochondria in bone and muscle progenitor cells [ 94 ]. In these cells, TNAP inhibition increased mitochondrial respiration and ATP production [ 94 ], providing molecular evidence to understand why TNAP-deficient mice, sheep and humans have mitochondria with disorganized cristae and/or reduced muscle strength [ 15 , 94 , 103 ]. Whether these effects are associated or not with changes in the creatine phosphorylation status is unknown but deserves investigation.…”