Neuron subset-specific Pten deletion induces abnormal skeletal activity in mice.
Individuals with a history of epilepsy are at higher risk for bone fractures compared to the general population. Although clinical studies support an association between low bone mineral density (BMD) and anti-seizure medications, little is known on whether a history of seizures is linked to altered bone health. Therefore, in this study we tested the hypothesis that bone mass, morphology, and bone mineralization are altered by seizures in genetically epileptic animals and in animals subjected to an episode of status epilepticus. In this study, we used NS-Pten conditional knockout mice (a well-studied genetic model of epilepsy). We used microCT analysis to measure BMD, morphology, and mineralization in NS-Pten+/+(wildtype) and NS-Pten-/-(knockout) mice at 4 and 8weeks, as well as adult Kv4.2+/+and Kv4.2-/-mice. We measured BMD, bone morphology, and mineralization in adult NS-Pten+/+mice that received status epilepticus through kainic acid (20mg/kg intraperitoneal). Further, we measured locomotion for NS-Pten+/+and NS-Pten-/-mice at 4 and 6weeks. We found that NS-Pten-/-mice exhibited low BMD in the tibial metaphysis and midshaft compared to non-epileptic mice. Morphologically, NS-Pten-/-mice exhibited decreased trabecular volume fraction, and endocortical expansion in both the metaphyeal and diaphyseal compartments. In the midshaft, NS-Pten-/-mice exhibited reduced tissue mineral density, indicating impaired mineralization in addition to morphological deficits. NS-Pten-/-mice exhibited hyperactivity in open field testing, suggesting low bone mass in NS-Pten-/-mice was not attributable to hypoactivity. Differences in BMD were not observed following kainate-induced seizures or in the Kv4.2-/-model of seizure susceptibility. Our findings suggest that deletion of Pten in the brain results in impaired bone mass and mineralization, which may contribute to weaker bones and thereby a higher fracture risk.
Department of Psychology and Neuroscience, Baylor University, Waco, TX 76798, USA; Institute of Biomedical Sciences, Baylor University, Waco, TX 76798, USA. Electronic address: joaquin_lugo@baylor.edu.
Joaquin N
JN
Lugo
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98104, USA.
Marjorie H
MH
Thompson
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98104, USA.
Philippe
P
Huber
Institute of Biomedical Sciences, Baylor University, Waco, TX 76798, USA.
Gregory
G
Smith
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98104, USA.
Ronald Y
RY
Kwon
D000367:Age Factors; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001847:Bone Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005106:Exploratory Behavior / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D017880:Limb Deformities, Congenital / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010009:Osteochondrodysplasias / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D012640:Seizures / Q000139:chemically induced; D051672:Shal Potassium Channels / Q000172:deficiency / Q000235:genetics
D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D051672:Shal Potassium Channels; D051059:PTEN Phosphohydrolase; D007608:Kainic Acid
BMD; Epilepsy; Fracture; Osteoporosis; PI3K; Seizure, neurodevelopmental disorder; mTOR