Ovariectomy increases RANKL protein expression in bone marrow adipocytes of C3H/HeJ mice

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Abstract
Estrogen deficiency induces bone loss by increasing bone resorption, in part, through upregulation of receptor activator of nuclear factor κB ligand (RANKL). RANKL is secreted by osteoblasts and osteocytes, but more recently also bone marrow (pre-)adipocytes have been shown to express RANKL. Estrogen deficiency increases bone marrow adipose tissue (BMAT). The aim of this study was to determine the effect of ovariectomy on RANKL protein expression by bone marrow adipocytes in C3H/HeJ mice. 14 weeks old, female C3H/HeJ mice (n=20) were randomized to sham surgery (Sham) or ovariectomy (OVX). After 4 weeks animals were euthanized. BMAT volume fraction (Ad.V/Ma.V) was quantified by polyoxometalate-based contrast enhanced nanoCT. The percentage of RANKL positive bone marrow adipocytes (RANKL.Pos.N.Ad/N.Ad) and the percentage of RANKL positive osteoblasts covering the bone surface (RANKL.Pos.B.Pm/B.Pm) were quantified in the distal metaphysis of immunohistochemically stained sections of the left femora. The effects of OVX were analyzed by Student's t-test or Mann-Whitney U test. RANKL was detected in osteoblasts, osteocytes and bone marrow adipocytes. OVX significantly increased mean RANKL.Pos.N.Ad/N.Ad (mean±SD: Sham: 42±18%; OVX: 62±14%; P = 0.029), as well as Ad.V/Ma.V (median (IQR): Sham: 1.4 (4.9)%; OVX: 7.2 (7.3)%: P = 0.008), compared to sham surgery. We show that ovariectomy increased both the percentage of RANKL positive bone marrow adipocytes and the total BMAT volume fraction in C3H/HeJ mice. This way RANKL produced by bone marrow adipocytes could be an important contributor to ovariectomy induced bone loss in C3H/HeJ mice.
Funding Information
  • Amsterdam UMC (2013-01)
  • Hercules Foundation (AKUL 13/47)

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