Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation

J Clin Invest. 2021 Mar 1;131(5):e138935. doi: 10.1172/JCI138935.


Previous studies have shown that nitric oxide (NO) supplements may prevent bone loss and fractures in preclinical models of estrogen deficiency. However, the mechanisms by which NO modulates bone anabolism remain largely unclear. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing arginine, the sole precursor for nitric oxide synthase-dependent (NOS-dependent) NO synthesis. Moreover, ASL is also required for channeling extracellular arginine to NOS for NO production. ASL deficiency (ASLD) is thus a model to study cell-autonomous, NOS-dependent NO deficiency. Here, we report that loss of ASL led to decreased NO production and impairment of osteoblast differentiation. Mechanistically, the bone phenotype was at least in part driven by the loss of NO-mediated activation of the glycolysis pathway in osteoblasts that led to decreased osteoblast differentiation and function. Heterozygous deletion of caveolin 1, a negative regulator of NO synthesis, restored NO production, osteoblast differentiation, glycolysis, and bone mass in a hypomorphic mouse model of ASLD. The translational significance of these preclinical studies was further reiterated by studies conducted in induced pluripotent stem cells from an individual with ASLD. Taken together, our findings suggest that ASLD is a unique genetic model for studying NO-dependent osteoblast function and that the NO/glycolysis pathway may be a new target to modulate bone anabolism.

Keywords: Bone Biology; Metabolism; Mouse models; Nitric oxide; Osteoclast/osteoblast biology.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Argininosuccinic Aciduria / genetics
  • Argininosuccinic Aciduria / metabolism*
  • Argininosuccinic Aciduria / pathology
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Cell Differentiation*
  • Child
  • Disease Models, Animal
  • Female
  • Glycolysis*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Nitric Acid / metabolism*
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology


  • Nitric Acid