Human bone marrow adipocytes support dexamethasone-induced osteoclast differentiation and function through RANKL expression

Goto, Hisataka; Osaki, Makoto; Fukushima, Tatsuya; Sakamoto, Kazutaka; Hozumi, Akira; Baba, Hideo; Shindo, Hiroyuki

doi:10.2220/biomedres.32.37

Cited by 49 publications

(37 citation statements)

References 31 publications

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“…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. These observations are in agreement with those of this study and demonstrate that adipocytes increase osteoclastogenesis via the OPG/RANKL/RANK system in the bone microenvironment.…”

Section: Discussionmentioning

confidence: 92%

“…Oshima et al (19) demonstrated that adiponectin induced by cytokines secreted by adipocytes directly suppresses bone-resorption activity by inhibiting osteoclastogenesis. However, observations of Goto et al (20) demonstrate that primary human bone marrow adipocytes promote osteoclast differentiation and activities. Leptin, an adipocyte-derived cytokine, has been found to function as a negative regulator of bone mass in a mouse model (21).…”

Section: Discussionmentioning

confidence: 97%

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

Hang

et al. 2013

Molecular Medicine Reports

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Abstract. Obesity is markedly associated with abnormal bone density indicating the importance of adipocytes in bone metabolism. However, the specific function of adipocytes remains unclear, with marked discrepancies in observations of previous studies. In the present study, the effect of adipocytes on osteoblasts/osteoclasts was analyzed. A mouse model of obesity was established and an in vitro co-culture system was utilized containing adipocyte and MC3T3/RAW 264.7 cells in a Transwell plate. Compared with control mice, obese mice exhibited low body weight and bone mineral density of the tibia and fat cells were observed to accumulate in bone marrow. MC3T3/RAW 264.7 cells were co-cultured with adipocytes and the mRNA and protein expression of alkaline phosphatase and osteocalcin was found to be decreased in MC3T3-E1 cells and mRNA and protein expression of tartrate-resistant acid phosphatase and cathepsin K was significantly increased in RAW 264.7 cells. In addition, the effect of adipocytes on the osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL)/RANK system indicated that the RANKL/OPG ratio secreted by osteoblasts increased and RANK expression by osteoclasts increased, leading to increased osteoclastogenesis. These results indicate that bone metabolism is impaired in obese mice leading to decreased osteoblastogenesis and marked increases in osteoclastogenesis and low bone mass. IntroductionObesity is becoming increasingly prevalent, leading to reduced life expectancy and increased health problems (1). High body mass index (BMI) is associated with various diseases, including cardiovascular, obstructive sleep apnea, diabetes mellitus type 2, specific types of cancer and osteoarthritis (2). Bone metabolism is also abnormal in obesity (3) and positive and negative factors have been identified to be associated with bone health status (4-6). A number of previous studies have revealed that obesity stimulates bone formation by inhibiting apoptosis. A recent study demonstrated that high BMI prevents normal bone fracture and osteoporotic fracture in various age groups and genders (7). By contrast, it has also been reported that osteoporosis occurs in obese individuals (8). These inconsistencies may be due to the use of different animal models in each study.Adipose tissue, a large endocrine organ, secretes a number of hormones that affect bone metabolism. Adipocytes in the bone marrow microenvironment differentiate from bone marrow mesenchymal cells and secrete cytokines which affect osteoblast and osteoclast levels in bone marrow. The effect of adipocytes on osteoblasts/osteoclasts remains controversial.The aim of the present study was to identify the function of adipocytes in the bone marrow microenvironment. To analyze the biological foundations of bone metastasis in obesity, a high-fat diet was selected to establish a mouse model of obesity (9). The results indicate that adipocytes accumulate in the bone marrow environment and affect bone turnover and osteoblast/osteoclast differentiation....

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

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

Hang

et al. 2013

Molecular Medicine Reports

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“…Considering that BMSCs are the precursors of osteoblasts, adipogenesis in the bone marrow limits the pool of osteoblasts, however, recent studies have indicated that it also potentiates bone metabolism through secretion of the factors such as insulin, insulin-like growth factor, and leptin (5,17,18,24). In fact, our previous observations demonstrated that bone marrow-derived adipocytes expressed the RANKL gene transcripts, whose level was up-regulated by TNF-α and dexamethasone (10,11,15). Therefore, in the present study, we aimed to examine the role of adipogenic conversion of BMSCs in osteoclastogenesis in vitro, focusing on the production of RANKL.…”

Section: Discussionmentioning

confidence: 97%

“…Total protein concentration was determined by the BCA protein assay (Pierce, Rockford, IL). Proteins (8 or 16 μg) were electrophoresed through an SDSpolyacrylamide gel and were electrophoretically is mediated by augmented expression of RANKL in adipocytes (10,11,15). These lines of evidence also suggest that adipogenic differentiation of BMSCs in the bone marrow might stimulate osteoclastogenesis.…”

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confidence: 98%

Potentiation of osteoclastogenesis by adipogenic conversion of bone marrowderivedmesenchymal stem cells

Mori¹,

Suzuki²,

Hozumi³

et al. 2014

Biomed. Res.

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Bone marrow-derived mesenchymal stem cells (BMSCs) are the indispensable component of the bone marrow, being the common precursors for adipocytes and osteoblasts. We show here that adipogenic differentiation resulted in increase in the production of adipocyte markers, such as adiponectin, fatty-acid binding proteins (FABP4), peroxisome proliferator-activated receptor γ (PPARγ), as well as the receptor activator of nuclear-κB ligand (RANKL). Co-culture of osteoclast precursors (OCPs) with BMSCs-derived adipocytes significantly enhanced osteoclast differentiation with low-dose RANKL, whose levels alone could not promote osteoclastogenesis. These results demonstrate for the first time that adipogenic differentiation of BMSCs plays a pivotal role in maintaining bone homeostasis.Bone homeostasis is maintained by various types of cells, such as osteoblasts and osteoclasts, which are differentiated from the different stem cells in the bone marrow (2,4,33,34). While osteoclasts are derived from hematopoietic stem cells (HSCs), osteoblasts are differentiated from bone marrow-derived mesenchymal stem cells (BMSCs). Therefore, harmonized coordination of the activities of these two stem cell compartments in the bone marrow is indispensable for bone homeostasis. In contrast, bone remodeling is regulated by the balance between osteogenesis and osteoclastogenesis (12,14,30,32,36). Osteoclasts are the central player in osteoclastogenesis, which are derived from monocytes in contact with osteoblasts through the interaction of receptor activator of nuclear-κB on osteoclast precursors and the receptor activator of nuclear-κB ligand (RANKL) expressed on osteoblasts (1,13,22,26,35). As a consequence, osteogenic differentiation from BMSCs is now recognized as an essential part integrated into bone remodelling. Accumulating evidences have also suggested that adipogenesis could play a significant role in bone metabolism (5,8,9,17,24,28,29). For example, since adipocytes and osteoblasts have the same ancestor, osteoblastogenesis and adipogenesis in the bone marrow are regulated in an opposite way, indicating that adipogenic conversion results in a reduction in osteoblast pool (24). As an endocrine organ, adipose tissue secretes adipokines, such as leptin and adiponectin, which may suppress the functions of osteoblasts (5,17,18). More recently, age-related fat accumulation and osteoporosis have been extensively discussed, and it is hypothesized that age-related bone marrow adiposity could accelerate osteoclastogenesis (3,17,27,31,38). Thus, it is highly likely that adipocytes in the bone marrow may have a positive interaction in osteoclastogenesis. In fact, our recent studies demonstrated that the primary human bone marrow adipocytes stimulate TNF-α or dexamethasone-induced osteoclast differentiation, which

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“…In the bone marrow space, there is a large quantity of mature adipocytes that are possible candidates for adipokine secretion. Considering the enclosed nature of the bone marrow space, intramedullary adipocytes may be involved in bone metabolism, as we previously reported that bone marrow adipocytes express receptor activator of nuclear factor kappa-B ligand (RANKL) and support osteoclast differentiation (5,8). Plasminogen activator inhibitor-1 (PAI-1), one of the adipokines secreted by adipocytes (1), suppresses fibrinolysis by binding tissue-type plasminogen activator (t-PA), and a relationship between PAI-1 and thrombosis or hypercoagulation has been suggested.…”

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confidence: 99%

<b>Steroid changes adipokine concentration in the blood and bone marrow </b><b>fluid </b>

Fukushima¹,

Hozumi²,

Tomita³

et al. 2016

Biomed. Res.

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Our previous study has shown that plasminogen activator inhibitor 1 (PAI-1) gene expression and secretion from bone marrow adipocytes increased markedly with dexamethasone administration. The purpose of the present study was to measure the secretion of various adipokines from human bone marrow and blood, and investigate how adipokine secretion changes in a steroid environment. Human blood and bone marrow fluid were collected from a steroid treatment group and a control group during hip replacement surgery, and an enzyme-linked immunosorbent assay (ELISA) was used to measure the adiponectin, leptin, and PAI-1 levels. Adiponectin and leptin showed no significant differences between bone marrow and blood levels, but PAI-1 was significantly higher in bone marrow. The steroid treatment group had higher levels of leptin and PAI-1 in both the blood and bone marrow than the control group. PAI-1 was present at high concentrations in the bone marrow and increased by steroid treatment. High levels of PAI-1 in bone marrow may influence intraosseous hemodynamics and may induce necrotic bone disorders.

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Human bone marrow adipocytes support dexamethasone-induced osteoclast differentiation and function through RANKL expression

Cited by 49 publications

References 31 publications

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

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

Potentiation of osteoclastogenesis by adipogenic conversion of bone marrowderivedmesenchymal stem cells

<b>Steroid changes adipokine concentration in the blood and bone marrow </b><b>fluid </b>

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