Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose

Abstract

Synthetic glucocorticoids (GCs) are widely used in the variety of dosages for treatment of premature infants with chronic lung disease, respiratory distress syndrome, allergies, asthma, and other inflammatory and autoimmune conditions. Yet, adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Conversely, 2-oxoglutarate (2-Ox), a precursor of glutamine, glutamate, and collagen amino acids, exerts protective effects on bone development. Our aim was to elucidate the effect of dietary administered 2-Ox on bone loss caused by neonatal treatment with clinically relevant maximal therapeutic dexamethasone (Dex) dose. Long bones of neonatal female piglets receiving Dex, Dex+2-Ox, or untreated were examined through measurements of mechanical properties, density, mineralization, geometry, histomorphometry, and histology. Selected hormones, bone turnover, and growth markers were also analyzed. Neonatal administration of clinically relevant maximal dose of Dex alone led to over 30% decrease in bone mass and the ultimate strength ( P < 0.001 for all). The length (13 and 7% for femur and humerus, respectively) and other geometrical parameters (13-45%) decreased compared to the control ( P < 0.001 for all). Dex impaired bone growth and caused hormonal imbalance. Dietary 2-Ox prevented Dex influence and vast majority of assessed bone parameters were restored almost to the control level. Piglets receiving 2-Ox had heavier, denser, and stronger bones; higher levels of growth hormone and osteocalcin concentration; and preserved microarchitecture of trabecular bone compared to the Dex group. 2-Ox administered postnatally had a potential to maintain bone structure of animals simultaneously treated with maximal therapeutic doses of Dex, which, in our opinion, may open up a new opportunity in developing combined treatment for children treated with GCs. Impact statement The present study has showed, for the first time, that dietary 2-oxoglutarate (2-Ox) administered postnatally has a potential to improve/maintain bone structure of animals simultaneously treated with maximal therapeutic doses of dexamethasone (Dex). It may open the new direction in searching and developing combined treatment for children treated with glucocorticoids (GCs) since growing group of children is exposed to synthetic GCs and adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Currently proposed combined therapies have numerous side effects. Thus, this study proposed a new direction in combined therapies utilizing dietary supplementation with glutamine derivative. Impairment caused by Dex in presented long bones animal model was prevented by dietary supplementation with 2-Ox and vast majority of assessed bone parameters were restored almost to the control level. These results support previous thesis on the regulatory mechanism of nutrient utilization regulated by glutamine derivatives and enrich the nutritional science.

Subsequent somatic axis and bone tissue metabolism responses to a low-zinc diet with or without phytase inclusion in broiler chickens

“…After the geometric measurements, the sample of proximal end of each tibia with no visible lesions and degenerative changes were subjected to histology. Sagittal sections containing epiphysis and metaphysis cartilages were taken from the middle of the lateral tibial condyle strictly adhering to the previously described method and equipment [ 32 ]. Five sections from each tibiae were cut from each individual broiler chicken with a microtome (Microm HM 360, Microm, Walldorf, Germany).…”

Glutamine Metabolism Is Essential for Stemness of Bone Marrow Mesenchymal Stem Cells and Bone Homeostasis

“…2-Oxoglutarate (2-Ox), a precursor of glutamine, has been identified to promote the thickness of cancellous bone, growth plate, and articular cartilage in fundectomy-induced osteopenic bone [153]. It was also applied in osteoporosis induced by glucocorticoid treatment in premature infants with inflammatory and autoimmune disorders, which improved levels of growth hormone and osteocalcin concentration and preserved microarchitecture of trabecular bone [154].…”

The Protective Role of Alpha-Ketoglutaric Acid on the Growth and Bone Development of Experimentally Induced Perinatal Growth-Retarded Piglets

“…However, this anabolic and anti-catabolic effect of AKG is consistent with the results of numerous previous studies. The protective properties of AKG (glutamine precursor), as a nutritional supplement, against the many negative effects of dexamethasone have been demonstrated in numerous previous experiments [ 5 , 10 , 29 , 56 , 61 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Nevertheless, such contrasting results with regards to the action of AKG, as those observed in our piglets, perinatally treated with Gc, have never been noted before.…”

“…Compact bone mineral density (BMDc) was assessed at the midpoint of the bone diaphysis. Trabecular bone mineral density (BMDt) was measured in the distal metaphysis with the scan positioned just below the calcification zone of the growth plate [ 61 ].…”