Neuropeptide Y mediates glucocorticoid-induced osteoporosis and marrow adiposity in mice.

UNLABELLED: Increased neuropeptide Y (NPY) expression occurred in the glucocorticoid-induced osteoporotic skeleton. NPY knockout mice exhibited a minor response to the glucocorticoid-mediated exacerbation of bone accretion and fatty marrow pathogenesis. NPY deletion restored SITR1 signaling and enhanced PPARγ ubiquitination of bone tissue, an alternative strategy for ameliorating glucocorticoid-induced skeletal deterioration.
INTRODUCTION: Glucocorticoid excess is observed to worsen the pathogenesis of osteoporosis and fatty marrow. This study was undertaken to investigate the contribution of neuropeptide Y (NPY) to glucocorticoid-induced bone loss and marrow adiposity.
METHODS: NPY knockout and wild-type mice were administered methylprednisolone for four consecutive weeks. Bone mineral density, microarchitecture, and calcein-labeled mineral acquisition were quantified by μCT, dual energy X-ray absorptiometry, and histomorphometry. Expression of osteogenic and adipogenic markers and acetylation states of PPARγ were detected by RT-quantitative PCR, immunoprecipitation, and immunoblotting.
RESULTS: High NPY levels were associated with glucocorticoid-induced trabecular bone deterioration and marrow fat accumulation. Mice lacking NPY had high bone mass concomitant with spacious trabecular and cortical bone microstructure. NPY deletion shielded skeletal tissues from the glucocorticoid-induced impediment of bone mass, trabecular morphometric characteristics, mineral accretion activity, and fatty marrow development. Ex vivo, NPY deficiency sustained osteogenic differentiation capacity and curtailed the glucocorticoid-mediated escalation of adipocyte formation reactions of primary bone-marrow mesenchymal cells. NPY deletion appeared to modulate Y1 and Y2 receptors, sirtuin 1, ERK, and p38 signaling pathways, an effect that facilitated hypoacetylation and ubiquitination of adipogenic transcription factor PPARγ in the skeletal tissues exposed to glucocorticoid stress.
CONCLUSIONS: NPY mediates the glucocorticoid-induced disturbance of mineral accretion and marrow adipogenesis through post-translational modification of PPARγ. This study brings a new molecular insight into the disintegration of adipogenic and osteogenic activities within glucocorticoid-mediated osteoporotic skeletons. Control of NPY is an alternative strategy to ameliorate glucocorticoid-induced bone destruction and fatty marrow.