Bone Marrow Adipose Tissue Research Articles

Sialoglycoprotein isolated from Carassius auratus eggs promotes osteogenesis by stimulating mesenchymal stem cells to commit to osteoblast differentiation.

In this study, we explore whether the pro-osteogenic effects of sialoglycoprotein from Carassius auratus eggs (Ca-SGP) involve mesenchymal stem cells (MSCs). Ovariectomized osteoporotic mice treated with Ca-SGP had increased bone formation and reduced bone marrow adipose tissue. As MSCs are common progenitors of osteoblasts and adipocytes, we isolated MSCs from Ca-SGP-treated mice and found that they tended to differentiate into osteoblasts over adipocytes confirmed by Alizarin red and Oil red O staining. This change was seen at the gene and protein level. To further explore the effect of Ca-SGP on MSCs, we isolated MSCs from healthy mice and treated them with Ca-SGP in vitro. We discovered that Ca-SGP promoted MSC differentiation to osteoblasts. In addition, Ca-SGP promoted osteogenesis and reduced the fat in marrow cavity of adolescent mice. For the first time, our results demonstrate that Ca-SGP promotes osteogenesis via stimulating MSCs to commit to osteoblasts. Graphical Abstract ᅟ.

Glucocorticoids and Body Fat Inversely Associate With Bone Marrow Density of the Distal Radius in Healthy Youths.

Elevated bone marrow adipose tissue (BMAT) is associated with lower bone quality, higher fracture rates, and an unfavorable overall metabolic profile. Apart from age, particularly glucocorticoids (GC), body fat, and diet are discussed to influence BMAT. We hypothesized that already in healthy youths, higher fat intake, higher fat mass index (FMI), and higher GC secretion, still within the normal range, may associate with increased BMAT. In a subsample of healthy 6- to 18-year-old participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study, peripheral quantitative CT of the nondominant proximal forearm was used to determine bone marrow density of the distal radius as an inverse surrogate parameter for BMAT. In those participants (n = 172) who had collected two, 24-hour urines within around one year before bone measurement, major urinary GC metabolites were measured by gas chromatography-mass spectrometry and summed up to assess daily adrenal GC secretion (ΣC21). Dietary intake was assessed by 3-day weighed dietary records. FMI was anthropometrically calculated. Separate multiple linear regression models were used to analyze the relationships of ΣC21, FMI, and fat intake with BMAT. After controlling for confounders, such as age, energy intake, and forearm muscle area, ΣC21 (β = -0.042) and FMI (β = -0.002) showed inverse relationships with bone marrow density (P < 0.05), whereas fat intake did not associate significantly. Our results indicate that already a moderately elevated GC secretion and higher body fatness during adolescence may adversely impact BMAT, an indicator for long-term bone health.

The development of bone marrow adipose tissue

Adipose tissue, once viewed as a form of connective tissue and the storage of fat, has now been considered as an endocrine organ of energy homeostasis. Bone marrow is a vital organ in our body and takes up 4% of body mass. It is responsible for creating hematopoietic cells, marrow adipose tissue, and supportive stromal cells. Mesenchymal stem cells in bone marrow can differentiate to both osteoblasts and adipocytes. Studies show that the adipose tissue in the bone marrow has negative influence on bone development. And the differentiation of the adipocytes in bone marrow can be controlled by the regulation of PPARγ, which is a member of the nucleus receptor family. In another word, the absence of PPARγ in the bone marrow can be beneficial for bone development. Moreover, the osteogensis can also be regulated by Cbfβ which is negatively correlated with adipogensis. In all kinds of adipose tissue, brown adipose tissue is distinct from others. It is triggered in cold conditions and release heat energy. Overexpression of PRDM16 in myoblasts can induce brown adipose.

Correction of QCT vBMD using MRI measurements of marrow adipose tissue.

Quantitative computed tomography (QCT) measurements of volumetric bone mineral density (vBMD) are subject to errors due to variations in the amount of bone marrow adipose tissue (BMAT). The purpose of our study was to describe and validate a novel method to correct lumbar spine trabecular vBMD measurements for BMAT using chemical shift-encoded magnetic resonance imaging (CSE-MRI). CSE-MRI measurements of proton density fat fraction (PDFF) were used to correct QCT spine vBMD measurements for BMAT based on the H2O and K2HPO4 basis set equivalent densities of bone, red and yellow bone marrow. BMAT corrected and uncorrected vBMD measurements of the L1 vertebra were compared with dual-energy QCT (DEQCT) measurements in 18 subjects (mean age: 68 y, range 60 to 93 y). A further 400 subjects (mean age: 53 y, range 21 to 82 y) had 120 kVp single-energy QCT and CES-MRI scans of L2-L4 and the data used to simplify the adipose tissue correction by deriving a linear equation between the CSE-MRI vBMD correction and fractional BMAT content. Application of the CSE-MRI derived vBMD correction changed the bias (95% limits of agreement) compared with DEQCT from 26.7 (11.0 to 42.4) mg/cm3 to 2.2 (-9.5 to 13.9) mg/cm3 at 80 kVp, and from 22.4 (3.3 to 41.6) mg/cm3 to 2.9 (-12.6 to 18.4) mg/cm3 at 120 kVp. Data for the 400 subjects gave the following relationship valid at 120 kVp: vBMD correction (mg/cm3) = -12.96 + 75.76 × BMAT. CSE-MRI measurements of PDFF can be used to correct for BMAT content and improve the accuracy of lumbar spine QCT vBMD measurements calibrated using a K2HPO4 phantom.

3T chemical shift-encoded MRI: Detection of altered proximal femur marrow adipose tissue composition in glucocorticoid users and validation with magnetic resonance spectroscopy.

Osteoporosis (OP) results in weak bone and can ultimately lead to fracture. Drugs such as glucocorticoids can also induce OP (glucocorticoid-induced osteoporosis [GIO]). Bone marrow adipose tissue composition and quantity may play a role in OP pathophysiology, but has not been thoroughly studied in GIO compared to primary OP. Chemical shift-encoded (CSE) MRI allows detection of subregional differences in bone marrow adipose tissue composition and quantity in the proximal femur of GIO compared to OP subjects and has high agreement with the reference standard of magnetic resonance spectroscopy (MRS). Prospective. In all, 18 OP and 13 GIO subjects. 3T. Multiple gradient-echo, stimulated echo acquisition mode (STEAM). Subjects underwent CSE-MRI in the proximal femurs, and for each parametric map regions of interest (ROIs) were assessed in the femoral head (fHEAD), femoral neck (fNECK), Ward's triangle (fTRIANGLE), and the greater trochanter (GTROCH). In addition, we compared CSE-MRI against the reference standard of MRS performed in the femoral neck and Ward's triangle. Differences between OP/GIO were investigated using the Mann-Whitney nonparametric test. Bland-Altman methodology was used to assess measurement agreement between CSE-MRI and MRS. GIO compared with OP subjects demonstrated: decreased monounsaturated fat fraction (MUFA) (-2.1%, P < 0.05) in fHEAD; decreased MUFA (-3.8%, P < 0.05), increased saturated fat fraction (SFA) (5.5%, P < 0.05), and decreased (-3.8 msec, P < 0.05) in fNECK; decreased proton density fat fraction (PDFF) (-15.1%, P < 0.05), MUFA (-9.8%, P < 0.05), polyunsaturated fat fraction (PUFA) (-1.8%, P < 0.01), increased SFA (11.6%, P < 0.05), and decreased (-5.4 msec, P < 0.05) in fTRIANGLE; and decreased (-1.5 msec, P < 0.05) in GTROCH. There was high measurement agreement between MRI and MRS using the Bland-Altman test. 3T CSE-MRI may allow reliable assessment of subregional bone marrow adipose tissue (bMAT) quantity and composition in the proximal femur in a clinically reasonable scan time. Glucocorticoids may alter the lipid profile of bMAT and potentially result in reduced bone quality. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:490-496.

Arachidonic Acid Induces Ferroptosis-Mediated Cell-Death in Multiple Myeloma

Mounting evidence suggests positive correlation of obesity and bone marrow (BM) adipogenesis with multiple myeloma (MM) initiation and progression. MM is more prevalent in patients with metabolic disorders including obesity and Gaucher's disease. Adipocytes constitute 70% of BM cellular volume in human adults making them one of the prominent players in MM progression. However, the underlying mechanisms involved remain unknown. Fat depots are increasingly recognized as the key endocrine organs for their ability to secrete various hormones (e.g. leptin, adiponectin, resistin), lipid substrates (polyunsaturated fatty acids), and cytokines (e.g. IL-6, IL-1, and TNFα). For example, leptin levels are increased in newly diagnosed MM patients that allow MM initiation by inhibiting NK T-cells (Favreaue 2017, Leukemia). Lipid substrates are also deregulated in the serum of cancer patients, including MM patients. These fatty acids are important initiators of many key downstream drug-targetable signaling pathways such as cyclooxygenase, cytochrome P450, and lipoxygenase pathways. In this study, we hypothesized that the changes in lipid profiles in MM patients contribute to disease progression.PPARγ is the key transcription factor that potentiates adipocyte differentiation and its key functions including lipid synthesis and transportation. We found that the BM adipose tissue (BMAT) fraction from MGUS, and SMM patients showed significantly increased PPARγ expression compared to the healthy donors. In vitro, MGUS and SMM BM stromal cells (BMSCs) showed increased adipogenic differentiation potential compared to the healthy donors. In-vitro, the proliferation of MM.1S human MM cells was significantly increased when co-cultured with BMSCs from MGUS/SMM patients compared to healthy donors. Taken together these data demonstrate a vicious cycle in which early stage MM cells and BM adipocytes support each other's growth.Multicomponent gene expression analysis of the BMAT from MGUS and MM patients showed altered genes involved mostly in fatty acid synthesis and metabolism. Lipidomics analysis revealed significantly decreased Arachidonic Acid (AA) levels in the BMSCs of SMM, the BM supernatant (BMS) of NDMM patients, and the blood serum of MGUS and SMM patients. This led us to hypothesize that increasing AA levels around MM cells may decrease MM progression.Physiological-range AA treatment of human MM cell lines, MM1S, H929, and U266, dose-dependently decreased proliferation and viability after 72-hours in all three cell lines. For in vivo studies, we generated humanized MM tumor growth in SCID mice by growing MM.1S cells in the intrascapular subcutaneous region for 3-weeks. Mice were then treated with either 100µg/g or 500µg/g of AA daily along with vehicle control via subcutaneous injection for 3-weeks near the tumor mass. Tumor volume continued to increase in vehicle control and 100 µg/g AA treatment groups but was significantly decreased in 500µg/g AA treatment group beginning 10-days after starting treatment. Gross examination of the tumor mass showed dramatically increased tumor necrosis. Flow cytometry analysis of CD138+ myeloma cells from non-necrotic part of the tumors showed significantly increased number of dead cells and the cells undergoing apoptosis in 500µg/g AA treatment group.AA is metabolized to primarily activate cyclooxygenase (COX), cytochrome P450 (CYP), and lipoxygenase (LOX) signaling pathways. Recent studies also show that AA induces ferroptosis, a programmed cell death in response to accumulation of lipid peroxides and mediated by iron (Kagan et al., 2017). To identify the primary apoptosis-inducing AA signaling pathway in MM cells, we used various inhibitors of each of these signaling pathways including ibuprofen, baicalein, BW B70C, 1-aminobenzotriazole, and ferrostatin. Among these compounds, ferrostatin completely rescued AA induced apoptosis in the human MM cells.Taken together, here we show that the adipogenesis is involved in myeloma pathogenesisis. Furthermore, AA signaling induces ferroptosis-mediated cell death in MM cells. Therefore, therapeutically targeting members of this signaling pathway is a potential novel treatment strategy for MM, especially in the MGUS and SMM stages. DisclosuresNo relevant conflicts of interest to declare.

The effect of PPARγ inhibition on bone marrow adipose tissue and bone in C3H/HeJ mice.

Bone marrow adipose tissue (BMAT) increases after menopause, and increased BMAT is associated with osteoporosis and prevalent vertebral fractures. Peroxisome proliferator-activated receptor-γ (PPARγ) activation promotes adipogenesis and inhibits osteoblastogenesis; therefore, PPARγ is a potential contributor to the postmenopausal increase in BMAT and decrease in bone mass. The aim of this study is to determine if PPARγ inhibition can prevent ovariectomy-induced BMAT increase and bone loss in C3H/HeJ mice. Fourteen-week-old female C3H/HeJ mice ( n = 40) were allocated to four intervention groups: sham surgery (Sham) or ovariectomy (OVX; isoflurane anesthesia) with either vehicle (Veh) or PPARγ antagonist administration (GW9662; 1 mg·kg-1·day-1, daily intraperitoneal injections) for 3 wk. We measured BMAT volume, adipocyte size, adipocyte number. and bone structural parameters in the proximal metaphysis of the tibia using polyoxometalate-based contrast enhanced-nanocomputed topogaphy. Bone turnover was measured in the contralateral tibia using histomorphometry. The effects of surgery and treatment were analyzed by two-way ANOVA. OVX increased the BMAT volume fraction (Sham + Veh: 2.9 ± 2.7% vs. OVX + Veh: 8.1 ± 5.0%: P < 0.001), average adipocyte diameter (Sham + Veh: 19.3 ± 2.6 μm vs. OVX + Veh: 23.1 ± 3.4 μm: P = 0.001), and adipocyte number (Sham + Veh: 584 ± 337cells/μm3 vs. OVX + Veh: 824 ± 113cells/μm3: P = 0.03), while OVX decreased bone volume fraction (Sham + Veh: 15.5 ± 2.8% vs. OVX + Veh: 7.7 ± 1.9%; P < 0.001). GW9662 had no effect on BMAT, bone structural parameters, or bone turnover. In conclusion, ovariectomy increased BMAT and decreased bone volume in C3H/HeJ mice. The PPARγ antagonist GW9662 had no effect on BMAT or bone volume in C3H/HeJ mice, suggesting that BMAT accumulation is regulated independently of PPARγ in C3H/HeJ mice.

Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton.

Intermittent administration of parathyroid hormone (PTH) stimulates bone formation in vivo and also suppresses the volume of bone marrow adipose tissue (BMAT). In contrast, a calorie-restricted (CR) diet causes bone loss and induces BMAT in both mice and humans. We used the CR model to test whether PTH would reduce BMAT in mice by both altering cell fate and inducing lipolysis of marrow adipocytes. Eight-week-old mice were placed on a control (Ctrl) diet or CR diet. At 12 wk, CR and Ctrl mice were injected daily with PTH (CR/PTH or Ctrl/PTH) or vehicle for 4 wk. Two other cohorts were CR and simultaneously injected (CR + PTH or CR + Veh) for 4 wk. CR mice had low bone mass and increased BMAT in the proximal tibias. PTH significantly increased bone mass in all cohorts despite calorie restrictions. Adipocyte density and size were markedly increased with restriction of calories. PTH reduced adipocyte numbers in CR + PTH mice, whereas adipocyte size was reduced in CR/PTH-treated mice. In contrast, osteoblast number was increased 3-8-fold with PTH treatment. In vitro, bone marrow stromal cells differentiated into adipocytes and, treated with PTH, exhibited increased production of glycerol and fatty acids. Moreover, in cocultures of bone marrow adipocyte and osteoblast progenitors, PTH stimulated the transfer of fatty acids to osteoblasts. In summary, PTH administration to CR mice increased bone mass by shifting lineage allocation toward osteogenesis and inducing lipolysis of mature marrow adipocytes. The effects of PTH on bone marrow adiposity could enhance its anabolic actions by providing both more cells and more fuel for osteoblasts during bone formation.-Maridas, D. E., Rendina-Ruedy, E., Helderman, R. C., DeMambro, V. E., Brooks, D., Guntur, A. R., Lanske, B., Bouxsein, M. L., Rosen, C. J. Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton.

Findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle.

Wnt10a is a member of the WNT family. Although deficiency of this gene causes symptoms related to teeth, hair, nails, and skin, we recently demonstrated a new phenotype of Wnt10a knockout (KO) mice involving bone and fat. The in vivo effect of the Wnt10a gene on bone and fat is unclear, and the relationship between bone/fat and muscle in Wnt10a signaling is also interesting. We aimed to evaluate the tissue changes in Wnt10a KO mice compared to wild-type mice and show the findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle. Trabecular bone loss in the lower limbs of Wnt10a mice and decreased bone mineralization were observed. The adipose tissue in bone marrow was also decreased, and adipocyte differentiation was reduced. The body fat mass in Wnt10a KO mice was decreased, and white adipocytes in subcutaneous fat were converted to beige adipocytes. The muscle weight of the lower limbs was not decreased despite trabecular bone loss, but Gdf8/myostatin expression was reduced in the subcutaneous fat and gastrocnemius muscles of Wnt10a KO mice. Thus, in vivo deletion of Wnt10a inhibited osteogenic activity, promoted beige adipogenesis of white adipocytes and maintained muscle mass. These results suggest that regulation of Gdf8 by Wnt10a may help maintain the muscle mass of Wnt10a KO mice. This study was the first to histologically evaluate the bone, fat and muscle phenotypes of Wnt10a KO mice. The results of this study, which were obtained by investigating the three tissues together, could influence the understanding of in vivo interactions involving the Wnt10a gene.

Regulation effects of melatonin on bone marrow mesenchymal stem cell differentiation

Melatonin's therapeutic potential has been highly underestimated because its biological functional roles are diverse and relevant mechanisms are complicated. Among the numerous biological activities of melatonin, its regulatory effects on pluripotent mesenchymal stem cells (MSCs), which are found in bone marrow stem cells (BMSCs) and adipose tissue (AD-MSC), have been recently proposed, which has received increasingly more attention in recent studies. Moreover, receptor-dependent and receptor-independent responses to melatonin are identified to occur in these cells by regulating signaling pathways, which drive the commitment and differentiation of MSCs into osteogenic, chondrogenic, or adipogenic lineages. Therefore, the aim of our current review is to summarize the evidence related to the utility of melatonin as a regulatory agent by focusing on its relationship with the differentiation of MSCs. In particular, we aimed to review its roles in promoting osteogenic and chondrogenic differentiation and the relevant signaling cascades involved. Also, the roles that melatonin and, particularly, its receptors play in these processes are highlighted.

Chronic Kidney Disease Is Associated With Greater Bone Marrow Adiposity

Bone marrow adiposity is associated with aging, osteoporosis, and reduced hematopoiesis, as well as anorexia nervosa, but little is known about the underlying mechanisms that affect marrow adiposity. Chronic kidney disease (CKD) may influence bone marrow adipose tissue (BMAT), possibly through loss of lean mass or higher circulating levels of sclerostin. To test these hypotheses, we investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) as a measure of kidney function and 1 H-MRS-based measurement of vertebral BMAT (L1 to L4) in 475 older adults from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. Mean BMAT was compared in those with eGFR >60 (n = 297) versus those with eGFR 45 to 60 (n = 120) or eGFR <45 (n = 58) using linear regression models. Participants had a mean age of 81.5 (SD 4.1) years, mean eGFR of 64.3 (SD 16.1) mL/min/1.734 cm2 , mean BMAT of 54.5% (SD 8.5); 48.2% were women. In unadjusted and adjusted models (age, visit window, gender, diabetes and visceral adipose tissue), BMAT was higher in those with eGFR <45 (adjusted mean 58.5%; 95% CI, 56.2 to 60.7) compared with those with eGFR >60 (adjusted mean 53.8%; 95% CI, 52.8 to 54.8) (p = 0.0002). BMAT did not differ in those with eGFR 45 to 60 (adjusted mean 54.3%; 95% CI, 52.8 to 55.9) compared with those with eGFR >60 (p = 0.58). In a subgroup of participants with serum sclerostin available (n = 253), additional adjustment for sclerostin attenuated the difference in adjusted mean vertebral BMAT between those with eGFR <45 versus >60 from 3.7% (p = 0.04) to 2.4% (p = 0.20). CKD stage 3b or worse was associated with greater bone marrow adiposity; this association may be partially mediated by sclerostin. © 2018 American Society for Bone and Mineral Research.

Chemical shift-encoded MRI for assessment of bone marrow adipose tissue fat composition: Pilot study in premenopausal versus postmenopausal women

ObjectTo quantify and compare subregional proximal femur bone marrow fat composition in premenopausal and postmenopausal women using chemical shift-encoded-MRI (CSE-MRI). Materials and methodsA multi gradient-echo sequence at 3 T was used to scan both hips of premenopausal (n = 9) and postmenopausal (n = 18) women. Subregional fat composition (saturation, poly-unsaturation, mono-unsaturation) was quantitatively assessed in the femoral head, femoral neck, Ward's triangle, greater trochanter, and proximal shaft in bone marrow adipose tissue and separately within red and yellow marrow adipose tissue. ResultsSignificant differences in fat composition in postmenopausal compared to premenopausal women, which varied depending on the subregion analyzed, were found. Within both whole and yellow marrow adipose tissue, postmenopausal women demonstrated higher saturation (+14.7% to +43.3%), lower mono- (−11.4% to −33%) and polyunsaturation (−52 to −83%) (p < 0.05). Within red marrow adipose tissue, postmenopausal women demonstrated lower fat quantity (−16% to −24%) and decreased polyunsaturation (−80 to −120%) in the femoral neck, greater trochanter, and Ward's triangle (p < 0.05). ConclusionCSE-MRI can be used to detect subregional differences in proximal femur marrow adipose tissue composition between pre- and post-menopausal women in clinically feasible scan times.

Osteogenic differentiation of mesenchymal stem cells modulated by a chemically modified super-hydrophilic titanium implant surface.

This study investigated the osteogenic functionality of multipotent mesenchymal stem cells (MSCs) modulated by a chemically modified super-hydrophilic titanium (Ti) bone implant surface to elucidate the biological mechanism underlying the bone healing capacity of this modified Ti surface. A microstructured Ti surface incorporating bioactive ions (in this study, phosphate (P) ions) was prepared by wet chemical treatment. The results showed that the hydrothermally obtained crystalline P-incorporated Ti surface (P surface) displayed long-term super-hydrophilicity (water contact angles <5°) during a 36-week observation period. The hydrophilic P surface enhanced early cellular functions and osteogenic differentiation of multipotent MSCs derived from mouse bone marrow and human adipose tissue. The expression of critical integrins affecting subsequent osteoblast function and osteoblast phenotype genes was notably upregulated in multipotent MSCs grown on the P surface compared with the commercially available grit-blasted microrough clinical oral implant surface. The P surface supported better cell spreading, focal adhesion and ALP activity of MSCs. These results indicate that a super-hydrophilic P-incorporated Ti surface accelerates implant bone healing by enhancing the early osteogenesis functions of multipotent MSCs.

Emerging Aspects of the Body Composition, Bone Marrow Adipose Tissue and Skeletal Phenotypes in Type 1 Diabetes Mellitus

Anthropomorphic measures among type 1 diabetic patients are changing as the obesity epidemic continues. Excess fat mass may impact bone density and ultimately fracture risk. We studied the interaction between bone and adipose tissue in type 1 diabetes subjects submitted to two different clinical managements: (I) conventional insulin therapy or (II) autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST). The study comprised 3 groups matched by age, gender, height and weight: control (C = 24), type 1 diabetes (T1D = 23) and type 1 diabetes treated with AHST (T1D-AHST = 9). Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by dual X-ray absorptiometry (DXA). 1H Magnetic resonance spectroscopy was used to assess bone marrow adipose tissue (BMAT) in the L3 vertebra, and abdominal magnetic resonance imaging was used to assess intrahepatic lipids (IHL), visceral (VAT) and subcutaneous adipose tissue (SAT). Individuals conventionally treated for T1D were more likely to be overweight (C = 23.8 ± 3.7; T1D = 25.3 ± 3.4; T1D-AHST = 22.5 ± 2.2 Kg/m2; p > 0.05), but there was no excessive lipid accumulation in VAT or liver. Areal BMD of the three groups were similar at all sites; lumbar spine TBS (L3) was lower in type 1 diabetes (p < 0.05). Neither SAT nor VAT had any association with bone parameters. Bone marrow adipose tissue (BMAT) lipid profiles were similar among groups. BMAT saturated lipids were associated with cholesterol, whereas unsaturated lipids had an association with IGF1. Overweight and normal weight subjects with type 1 diabetes have normal areal bone density, but lower trabecular bone scores. Adipose distribution is normal and BMAT volume is similar to controls, irrespective of clinical treatment.

Abstract 1808: The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice

Abstract Endoxifen, the predominant CYP2D6 metabolite of the selective estrogen receptor modulator (SERM) tamoxifen, is currently being developed as a novel anti-estrogen therapy for the treatment of estrogen receptor (ER)+ breast cancer. Genetic polymorphism of CYP2D6 is a predictor of response to tamoxifen in patients, implicating endoxifen as one of the most active and relevant tamoxifen metabolites. Breast cancer patients treated with adjuvant endocrine therapies including aromatase inhibitors (AIs) and SERMs often report unmanageable musculoskeletal toxicities that can result in treatment discontinuation. While ER binding affinity and anti-tumor effects have been established in preclinical models, the effects of endoxifen on the musculoskeletal system are not fully known. Twenty-week female C57BL/6 mice underwent sham surgery or ovariectomy (OVX) and were treated daily with vehicle, the AI letrozole, or the SERM endoxifen. Body composition was assessed prospectively by DXA. Bone indices and marrow adipose tissue volume were measured by μCT and muscle contractility of the extensor digitorum longus (EDL) was measured ex vivo. After eight weeks, trabecular bone volume fraction (BV/TV) decreased by 50% in OVX-vehicle and OVX-letrozole mice, whereas BV/TV increased threefold in endoxifen mice relative to sham-vehicle. Despite the presence of significantly more trabecular bone following endoxifen treatment, cortical bone analyses revealed impaired periosteal and endosteal expansion of bone, resulting in reduced polar moment of inertia, which is a measure of resistance to fracture. Uterine weight increased significantly in endoxifen-treated mice relative to all OVX groups, similar to what is observed with tamoxifen treatment. Peripheral body fat, bone marrow adipose tissue, and circulating leptin were reduced by endoxifen, suggesting that the drug may elicit positive systemic metabolic effects. At the termination of the study, muscle-specific force was reduced in OVX-endoxifen mice relative to sham-vehicle, OVX-vehicle, and OVX-AI mice, despite no change in muscle mass. While endoxifen shows promise as a potent anti-estrogen therapy for the treatment of ER+ breast cancer, it may be important to monitor patients for endometrial proliferation, morphological changes in bone that increase fracture risk, and for musculoskeletal side effects that could reduce drug compliance. Citation Format: Laura Wright, Khalid Mohammad, Theresa Guise. The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1808.

Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma.

Obesity has become a global epidemic influencing the establishment and progression of a wide range of diseases, such as diabetes, cardiovascular disease, and cancer. In 2016, International Agency for Research on Cancer reported that obesity is now associated with 13 different cancers, one of which is multiple myeloma (MM), a destructive cancer of plasma cells that predominantly reside in the bone marrow. Obesity is the accumulation of excess body fat, which causes metabolic, endocrine, immunologic, and inflammatory-like changes. Obesity is usually associated with an increase in visceral and/or subcutaneous fat; however, an additional fat depot that also responds to diet-induced changes is bone marrow adipose tissue (BMAT). There have been several studies over the past few decades that have identified BMAT as a key driver in MM progression. Adipocytes secrete numerous adipokines, such as leptin, adiponectin, resistin, adipsin, and visfatin, which when secreted at normal controlled levels have protective properties. However, in obesity these levels of secretion change, coupled with an increase in adipocyte number and size causing a profound and lasting effect on the bone microenvironment, contributing to MM cell growth, survival, and migration as well as potentially fueling bone destruction. Obesity is a modifiable risk factor making it an attractive option for targeted therapy. This review discusses the link between obesity, monoclonal gammopathy of undetermined significance (a benign condition that precedes MM), and myeloma, and the contribution of key adipokines to disease establishment and progression.

Bone Marrow Adipose Tissue and Skeletal Health.

To summarize and discuss recent progress and novel signaling mechanisms relevant to bone marrow adipocyte formation and its physiological/pathophysiological implications for bone remodeling. Skeletal remodeling is a coordinated process entailing removal of old bone and formation of new bone. Several bone loss disorders such as osteoporosis are commonly associated with increased bone marrow adipose tissue. Experimental and clinical evidence supports that a reduction in osteoblastogenesis from mesenchymal stem cells at the expense of adipogenesis, as well as the deleterious effects of adipocyte-derived signaling, contributes to the etiology of osteoporosis as well as bone loss associated with aging, diabetes mellitus, post-menopause, and chronic drug therapy. However, this view is challenged by findings indicating that, in some contexts, bone marrow adipose tissue may have a beneficial impact on skeletal health. Further research is needed to better define the role of marrow adipocytes in bone physiology/pathophysiology and to determine the therapeutic potential of manipulating mesenchymal stem cell differentiation.

Bone marrow adipose tissue: starving for attention

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Cross-talk between bone marrow and peripheral adipose tissue in man

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

18F]-FDG PET/CT imaging: A tool to reveal the metabolic functions of bone marrow adipose tissue

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)