Effects of short- and long-term glucocorticoid-induced osteoporosis on plasma metabolome and lipidome of ovariectomized sheep

Abstract

Background: Understanding the metabolic and lipidomic changes that accompany bone loss in osteoporosis might provide insights about the mechanisms behind molecular changes and facilitate developing new drugs or nutritional strategies for osteoporosis prevention. This study aimed to examine the effects of short-or long-term glucocorticoid-induced osteoporosis on plasma metabolites and lipids of ovariectomized (OVX) sheep. Methods: Twenty-eight aged ewes were divided randomly into four groups: an OVX group, OVX in combination with glucocorticoids for two months (OVXG2), and OVX in combination with five doses of glucocorticoids (OVXG5) to induce bone loss, and a control group. Liquid chromatography-mass spectrometry untargeted metabolomic analysis was applied to monthly plasma samples to follow the progression of osteoporosis over five months. Results: The metabolite profiles revealed significant differences in the plasma metabolome of OVX sheep and OVXG when compared with the control group by univariate analysis. Nine metabolites were altered, namely 5methoxytryptophan, valine, methionine, tryptophan, glutaric acid, 2-pyrrolidone-5-carboxylic acid, indole-3carboxaldehyde, 5-hydroxylysine and malic acid. Similarly, fifteen lipids were perturbed from multiple lipid classes such as lysophoslipids, phospholipids and ceramides. Conclusion: This study showed that OVX and glucocorticoid interventions altered the metabolite and lipid profiles of sheep, suggesting that amino acid and lipid metabolisms are potentially the main perturbed metabolic pathways regulating bone loss in OVX sheep.

Intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats

“…Estrogen de ciency was shown to downregulate the expression of Runx2, resulting in bone loss and increased fracture risk [27]. In this study, female SD rats were used to establish an osteoporosis model after bilateral ovariectomy and mimics bone loss in the physiological state of female postmenopausal estrogen de ciency [28,29]. In this mature animal model, we con rmed that decreased BMD and bone loss by DEXA and Micro-CT occurred in femur at 12 weeks following OVX, consistent with our previous observation [22,30].…”

Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover

“…Additionally, avascular necrosis via an apoptotic mechanism of osteocytes and osteoblasts [66] and glucocorticoid-induced myopathy is considered to affect bone health and increase in falling risks [7]. Finally, glucocorticoids alter metabolites and lipid profiles, which potentially have a role in regulating bone loss [67,68].…”

Expression of Renal Vitamin D and Phosphatonin-Related Genes in a Sheep Model of Osteoporosis

“…The most common sheep models of osteoporosis are the 12 month post-operatively ovariectomized sheep and the 6 month ovariectomized sheep on a calcium and vitamin D deficient diet given glucocorticoids [ 4 ]. By using a combination of known osteoporosis-inducing factors including ovariectomy, glucocorticoid treatment and a low calcium diet, we have been able to establish a sheep model of osteoporosis in just 5 months [ 6 , 7 ], thus decreasing the housing, labor, and feed costs involved in model development. In this model, ovariectomy was found to increase the serum concentrations of C-terminal telopeptides of type I collagen (CTX-I, a bone resorption marker) and osteocalcin (bone turnover marker) compared with control sheep.…”

“…Additionally, femoral and lumbar spine bone density, and total and trabecular volumetric bone mineral density of the proximal tibia were lower in experimentally treated groups compared with the control groups, particularly for ovariectomized glucocorticoid treated ewes [ 6 ]. Amino acid and lipid metabolism was also found to be altered in ovariectomized and glucocorticoid treated sheep [ 7 ]. Similar changes have also been found in other ovine osteoporosis models [ 8 ].…”