64 research outputs found
NIK Stabilization in Osteoclasts Results in Osteoporosis and Enhanced Inflammatory Osteolysis
Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-ÎşB inducing kinase (NIK) controls activation of the alternative NF-ÎşB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-ÎşB pathway.Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-ÎşB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis.Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli
Geraniol attenuates osteoclast differentiation by suppressingNF-kB activity and expression of osteoclastogenic genes
Osteoporotic patients have lower bone mass due
to increased bone resorption by osteoclasts. The aim of this
study was to investigate the cytotoxic and antiosteoclastogenic
effects of geraniol, a natural monoterpene
on human CD14+ monocytes (ex vivo) and murine
RAW264.7 macrophages (in vitro) using alamar blue and
tartrate resistant acid phosphatase staining respectively. The
anti-osteoclastogenic activity of geraniol was further
explored by analyzing its effects on actin ring formation and
bone resorptive function of osteoclasts. Geraniol significantly
(p < 0.001) inhibited osteoclast formation in
CD14+ monocytes and RAW264.7 macrophages without
cytotoxicity. Moreover, reduced osteoclastogenesis in these
cells led to an arrest in actin ring formation and diminished
bone resorption. Analysis of underlying molecular
mechanisms revealed that geraniol alleviated NF-kB activity,
an indispensable upstream modulator of osteoclast formation.
Furthermore, expression of key osteoclastogenic
genes such as dendritic cell-specific transmembrane protein
(DC-STAMP) involved in cell-cell fusion and nuclear factor
of activated T-cells, cytoplasmic, calcineurin-dependent
1 (NFATc1), a master transcription factor essential for osteoclast differentiation was downregulated by geraniol.
These observations indicate that inhibition of osteoclast
differentiation is presumably one of the pharmacological
properties of geraniol.Grants from the University of Pretoria Vice Chancellor’s Postdoctoral Research Fellowship; RESCOM, University of Pretoria and the University of Pretoria’s Strategic Institutional Research Theme in Food, Nutrition and Well-being.http://link.springer.com/journal/442017-12-31hb2016Food ScienceHuman NutritionPhysiolog
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