Abstract
Studying effects of milk components on bone may have a clinical impact as milk is highly associated with bone maintenance, and clinical studies provided controversial associations with dairy consumption. We aimed to evaluate the impact of milk extracellular vesicles (mEVs) on the dynamics of bone loss in mice. MEVs are nanoparticles containing proteins, mRNA and microRNA, and were supplemented into the drinking water of mice, either receiving diet-induced obesity or ovariectomy (OVX). Mice receiving mEVs were protected from the bone loss caused by diet-induced obesity. In a more severe model of bone loss, OVX, higher osteoclast numbers in the femur were found, which were lowered by mEV treatment. Additionally, the osteoclastogenic potential of bone marrow-derived precursor cells was lowered in mEV-treated mice. The reduced stiffness in the femur of OVX mice was consequently reversed by mEV treatment, accompanied by improvement in the bone microarchitecture. In general, the RANKL/OPG ratio increased systemically and locally in both models and was rescued by mEV treatment. The number of osteocytes, as primary regulators of the RANKL/OPG system, raised in the femur of the OVX mEVs-treated group compared to OVX non-treated mice. Also, the osteocyte cell line treated with mEVs demonstrated a lowered RANKL/OPG ratio. Thus, mEVs showed systemic and local osteoprotective properties in two mouse models of bone loss reflected in reduced osteoclast presence. Data reveal mEV potential in bone modulation, acting via osteocyte enhancement and RANKL/OPG regulation. We suggest that mEVs could be a therapeutic candidate for the treatment of bone loss.
Highlights
Osteoporosis is a multifactorial disease characterized by low bone mass and structural deterioration of bone tissue, leading to fragility and increased risk of fractures (Rolland et al, 2008)
All parameters that changed in mice fed with the high refined carbohydratecontaining (HC) diet were reversed by milk extracellular vesicles (mEVs) treatment (Figure 1)
This model of obesity is characterized by no alteration in body weight gain (Supplementary Figure S1A), but an increase in visceral and subcutaneous adipose tissue (Supplementary Figure S1B) associated with increased leptin (Supplementary Figure S1C) in mice fed with HC diet
Summary
Osteoporosis is a multifactorial disease characterized by low bone mass and structural deterioration of bone tissue, leading to fragility and increased risk of fractures (Rolland et al, 2008). Obesity is characterized by an expansion of adipose tissue and chronic inflammation, usually developed from nutrient overloads (Greenberg and Obin, 2006). Pro-inflammatory cytokines from obesity-induced chronic inflammation disrupt the bone homeostasis by activating bone-resorbing cells and inhibiting osteoblasts (Ornstrup et al, 2015). These two scenarios, osteoporosis and obesity, are quite common to be observed in the population and closely related to bone loss development and, reduced bone quality
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