Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice

Abstract

Clinical evidence indicates that fat is inversely proportional to bone mass in elderly obese women. However, it remains unclear whether obesity accelerates bone loss. In this report we present evidence that increased visceral fat leads to inflammation and subsequent bone loss in 12-monthold C57BL/6J mice that were fed 10% corn oil (CO)-based diet and a control lab chow (LC) for 6 months. As expected from our previous work, CO-fed mice demonstrated increased visceral fat and enhanced total body fat mass compared to LC. The adipocyte-specific PPARγ and bone marrow (BM) adiposity were increased in CO-fed mice. In correlation with those modifications, inflammatory cytokines (IL-1β, IL-6, TNF-α) were significantly elevated in COfed mice compared to LC-fed mice. This inflammatory BM microenvironment resulted in increased superoxide production in osteoclasts and undifferentiated BM cells. In CO-fed mice, the increased number of osteoclasts per trabecular bone length and the increased osteoclastogenesis assessed exvivo suggest that CO diet induces bone resorption. Additionally, the up-regulation of osteoclastspecific cathepsin k and RANKL expression and down-regulation of osteoblast-specific RUNX2/ Cbfa1 supports this bone resorption in CO-fed mice. Also, COfed mice exhibited lower trabecular bone volume in the distal femoral metaphysis and had reduced OPG expression. Collectively, our results suggest that increased bone resorption in mice fed a CO-enriched diet is possibly due to increased inflammation mediated by the accumulation of adipocytes in the BM microenvironment. This inflammation may consequently increase osteoclastogenesis, while reducing osteoblast development in CO-fed mice.

Inhibiting myostatin signaling prevents femoral trabecular bone loss and microarchitecture deterioration in diet-induced obese rats

“…9,43 Consistent with these studies, our results showed that the HF diet induced significantly higher TNF-a and IL-6 concentrations in serum along with a trend toward elevated TRACP. TRACP is an osteoclastic bone resorption marker that has been reported to increase in mice fed a HF diet.…”

“…7,8 The potential mechanisms may involve the abundant adipokines and pro-inflammatory cytokines produced by adipose tissue, which can regulate bone metabolism. [9][10][11] Furthermore, marrow adipogenesis may be inversely related to osteoblastogenesis, 12,13 since adipocytes and bone-forming osteoblasts are derived from a common multipotential mesenchymal stem cell.…”

Adipocytes regulate the bone marrow microenvironment in a mouse model of obesity

“…However, an increasing number of studies have indicated that obesity in female mice is accompanied by bone loss (8,(13)(14)(15). This may be due to the role of adipose tissue as an endocrine organ, secreting pro-inflammatory cytokines, whose effects damage the trabecular bone (16). Therefore, the use of different mouse models in prevous studies may explain these inconsistencies.…”

“…Following this, adipocyte-secreted cytokines affected the OPG/RANKL/RANK trail system, resulting in a marked increase in osteoclast differentiation. Halade et al (16) reported that OPG secretion decreased and RANKL expression increased in osteoblasts stimulated with adipocyte-secreted factors. By contrast, Goto et al (20) demonstrated that adipocyte-secreted cytokines upregulated RANKL mRNA expression in osteoblasts, consistent with osteoclast differentiation in vitro.…”

Effects of obesity treatments on bone mineral density, bone turnover and fracture risk in adults with overweight or obesity

“…Interestingly, these fracture sites [7] differ from the fracture sites most commonly seen in osteoporosis, which are the wrist, upper arm, rib, hip and spine [7]. A number of possible contributors to compromised skeletal health in obesity have been proposed, including but not limited to reduced vitamin D bioavailability [9,14] and an inflammatory state that increases bone breakdown [15]. Moreover, individuals with obesity have a heightened risk of mobility impairment [16] and falls [17,18], due to factors such as poor compensatory stepping responses and postural instability [17] as well as intramuscular fat infiltration which reduces muscle strength [9,19,20].…”