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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #366895
Title: Activation of Nox4 is not required for OVX-induced osteoblast senescence and bone loss in mice

Author
item CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC)
item LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHAO, HAIJUN - Arkansas Children'S Nutrition Research Center (ACNC)
item WATT, JAMES - Louisiana State University
item RONIS, MARTIN J.J. - Louisiana State University

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 7/1/2019
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Ovariectomy (OVX) in rodents is a well-known animal model of osteoporosis of postmenopausal women. Despite current understanding of that estrogen deficiency plays a critical role in the pathophysiology of these conditions, the molecular mechanisms through which sex steroid deficiency induces osteopenia and osteoporosis are largely unknown. Prevention of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox)-dependent accumulation of oxidative stress may be one of approaches to potentially minimize bone loss due to conditions as sex steroid deficiency, aging or chronic alcohol. Using OVX and Nox4 gene knockout mouse models, we investigated the role Nox4 in OVX- or aging-induced bone loss and osteoblast senescence signaling. First, 6 month old wild type C57Bl mice were allocated to a sham control group, OVX, and OVX plus E2 treatment group for eight weeks. Bone mass in tibia was assessed by peripheral quantitative computerized tomography (pQCT) analysis. Moreover, bone turnover marker measurements, bone histology, western blots, real-time PCR and others were used for molecular signaling exploration. Significantly decreased bone mass including bone mineral density (BMD) and content (BMC) were found in OVX group compared with sham control (p<0.05), E2 treatment completely reversed OVX-induced bone loss. Serum bone turnover marker measurements revealed that E2 blocked significantly increased bone resorption markers TRAP5b and CTX-1in OVX group. Interestingly, we found significantly increased (p<0.05) senescence signaling in bone osteoblastic cells from OVX group, E2 blocked it. Analysis for molecular transduction indicated that OVX significantly activated p53, p21 and Nox4 expression, however, E2 only eliminated OVX-induced p53 and p21expression, but not Nox4. We next therefore investigated if Nox4 is dispensable for OVX-induced bone loss and senescence signaling in osteoblasts. Eight and eleven month old Nox4-/- female mice were ovariectomized, their bone mass and osteoblastic cell signaling were compared with respective age-matched Nox4-/- sham groups. We found significant bone loss, and increased bone osteoblastic cell senescence signaling occurred in Nox4-/- OVX mice compared with Nox4-/- sham operated animals. Moreover, we found significantly decreased bone mass and increased bone osteoblastic cell senescence signaling in one-year-old Nox4-/- sham mice compared to eight-month-old Nox4-/- sham mice. These data suggest that activation of Nox4 expression in bone osteoblastic cells may be dispensable for sex steroid deficiency- or aging-induced bone loss and accelerated senescence signaling.