Abstract
Adenosine is known to regulate bone production and resorption in humans and mice. Type 1 equilibrative nucleoside transporter (ENT1) is responsible for the majority of adenosine transport across the plasma membrane and is ubiquitously expressed in both humans and mice. However, the contribution of ENT1-mediated adenosine levels has not been studied in bone remodeling. With the recent identification of the importance of adenosine signaling in bone homeostasis, it is essential to understand the role of ENT1 to develop novel therapeutic compounds for bone disorders. Here we examined the effect of ENT1 deletion on bone density using X-ray, dual energy X-ray absorptiometry and micro-computerized tomography analysis. Our results show that bone density and bone mineral density is reduced in the lower thoracic and lumbar spine as well as the femur of old ENT1 null mice (>7 months) compared to wild-type littermates. Furthermore, we found increased mRNA expression of tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, in isolated long bones from 10 month old ENT1 null mice compared to wild-type mice. In addition, aged ENT1 null mice displayed severe deficit in motor coordination and locomotor activity, which might be attributed to dysregulated bone density. Overall, our study suggests that ENT1-regulated adenosine signaling plays an essential role in lumbar spine and femur bone density.
Highlights
Bone disorders including senile osteopenia, osteoporosis and diffuse idiopathic skeletal hyperostosis (DISH) are serious public health concerns of the aging population
The loss of ENT1 leads to progressive ectopic mineralization of the upper thoracic and cervical spinal cord resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans [18], the effect of ENT1 deletion on bone density in the lower portion of the spinal column and femur remained unknown
We examined the effect of ENT1 deletion on bone density, motor coordination, locomotor function as well as mRNA expression of genes associated with osteoclast activity
Summary
Bone disorders including senile osteopenia, osteoporosis and diffuse idiopathic skeletal hyperostosis (DISH) are serious public health concerns of the aging population. Based on cultured cell experiments, it has been determined that adenosine A1 receptor activation results in osteoclast differentiation [8,9,10,12]. A2A receptor activation inhibits osteoclast differentiation [11] and is important for osteoblast maturation [7]. Adenosine is transported across cellular membranes by nucleoside transporters In both humans and mice type 1 equilibrative nucleoside transporter (ENT1) is ubiquitously expressed and is responsible for the majority of adenosine transport [14]. We examined the effect of ENT1 deletion on bone density, motor coordination, locomotor function as well as mRNA expression of genes associated with osteoclast activity
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