Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia

Abstract

A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance. Mice with loss of function mutations in kit receptor (kitW/W-v) have no bone marrow adipocytes in tibia or lumbar vertebra. We therefore tested the hypothesis that marrow fat contributes to development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kitW/W-v mice. Mice were ovx at 4 weeks of age and sacrificed 4 or 10 weeks post-surgery. Body composition was measured at necropsy by dual-energy X-ray absorptiometry. Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography. Bone marrow adipocyte size and density, osteoblast- and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry. Ovx resulted in an increase in total body fat mass at 10 weeks post-ovx in both genotypes, but the response was attenuated in the in kitW/W-v mice. Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx. In contrast, marrow adipocytes were not detected in either intact or ovx kitW/W-v mice. However, ovx in WT and kitW/W-v mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters. In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice.

Morbid obesity attenuates the skeletal abnormalities associated with leptin deficiency in mice

“…Adipocytes and osteoblasts are derived from the same bone marrow mesenchymal precursor and a reciprocal association between osteoblast number and adipocyte number has often been noted, giving rise to the hypothesis that bone marrow adipocytes may either antagonize osteoblast production or, alternatively, generation of adipocytes precludes generation of osteoblasts (Akune, et al 2004). Other studies suggest that adipocyte and osteoblast number in bone marrow can be independently regulated (Iwaniec and Turner 2013; Menagh et al 2010). Bartell et al (2011) reported that intracerebroventricular administration of leptin to ob/ob mice increases expression of SP7, a transcription factor critical for osteoblast differentiation.…”

Development, regulation, metabolism and function of bone marrow adipose tissues

“…In contrast, cBMAT in distal tibia is similar between sexes 18, 21, 27 . As in humans, estrogen deficiency in rodents is a strong stimulus for BMAT development 18, 28 , and whereas ovariectomy increases cBMAT of distal tibia by ~30%, the expansion of proximal tibial rBMAT is far more extensive 18, 28 . Estrogen is not only necessary to restrain accumulation of BMAT, but exogenous administration of estrogen is sufficient to stimulate rapid loss of marrow adiposity in tibia 29 .…”

Marrow Adipose Tissue: Trimming the Fat

“…Specifically, removal of the pituitary gland in rats causes robust increases in MAT that are rescued by administration of exogenous growth hormone, but not intermittent PTH, 17β-estradiol, or IGF-1 [65]. Estrogen deficiency [66,67], FGF-21 [68] and glucocorticoids [69,70] also promote MAT formation. Of these, increases in circulating glucocorticoids may be necessary for MAT accumulation with CR [4].…”