Bone marrow adipose tissue

Bone marrow adipose tissue (BMAT), sometimes referred to as marrow adipose tissue (MAT), is a type of fat deposit in bone marrow. It increases in states of low bone density -osteoporosis, anorexia nervosa/ caloric restriction, skeletal unweighting such as that which occurs in space travel, and anti-diabetes therapies. BMAT decreases in anaemia, leukaemia, and hypertensive heart failure; in response to hormones such as oestrogen, leptin, and growth hormone; with exercise-induced weight loss or bariatric surgery; in response to chronic cold exposure; and in response to pharmacological agents such as bisphosphonates, teriparatide, and metformin. Bone marrow adipocytes (BMAds) originate from mesenchymal stem cell (MSC) progenitors that also give rise to osteoblasts, among other cell types. Thus, it is thought that BMAT results from preferential MSC differentiation into the adipocyte, rather than osteoblast, lineage in the setting of osteoporosis. Since BMAT is increased in the setting of obesity and is suppressed by endurance exercise, or vibration, it is likely that BMAT physiology, in the setting of mechanical input/exercise, approximates that of white adipose tissue (WAT). The first study to demonstrate exercise regulation of BMAT in rodents was published in 2014; Now, exercise regulation of BMAT has been confirmed in a human, adding clinical importance. Several studies demonstrated exercise reduction of BMAT which occurs along with an increase in bone quantity. Since exercise increases bone quantity, reduces BMAT and increases expression of markers of fatty acid oxidation in bone, BMAT is thought to be providing needed fuel for exercise-induced bone formation or anabolism. A notable exception occurs in the setting of caloric restriction: exercise suppression of BMAT does not yield an increase in bone formation and even appears to cause bone loss. Indeed, energy availability appears to be a factor in the ability of exercise to regulate BMAT.

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Bone marrow adipose tissue

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Quantitative approaches to unravel bone marrow adipocyte site-specificity and its implication in hematopoiesis

Josefine Catharina Pedersen Tratwal

Over the last decade, bone marrow (BM) adipose tissue (BMAT) has emerged as a distinct adipose depot with unique metabolic properties and effects both in homeostasis and in the progression of disease. We provide a first comprehensive review of existing and emerging technologies including accompanying challenges for the study of bone marrow adipocytes (BMAds). The recommendations specified through this consensus opinion for standardization of methodological approaches are imperative on our quest to uncover the meaning, the sense, and the significance of BMAds. Due to its challenging localization within the bone and its fragile nature, imaging methods provide powerful tools for ex vivo or in vivo BMAT quantification as well as characterization through lipid profiling. While isolation methods are still evolving in the pursuit of the BMAd and its progenitor, lineage tracing and BMAT (environmental, pharmacological, or pathological) modulation studies have identified two sub-populations of BMAds dependent on skeletal location in the hematopoietic red or fatty yellow marrow. We uncover changes to these compartments in the mouse skeleton with age or irradiation and bone marrow transplantation induced aplastic conversion of the marrow, through our novel imaging quantification tool for histological sections. Following this progression by magnetic resonance imaging in vivo emphasized a differential hematopoietic recovery within the long bones of mice. In order to delineate the subtle differences between BMAds of red and fatty marrow, we established first an adipocytic differentiation, and then a co-culture system to recapitulate the BM niche in vitro with the OP9 stromal cell line. Notably, Raman microspectroscopic analysis revealed nuances of lipid saturation levels previously reported in primary BMAds at the single droplet level that we propose is indicative of their maturation state. This may have implication for the documented differential hematopoietic support capacity of BMAds that we elucidate through co-culture with hematopoietic stem and progenitor cells. We were able to translate the established co-culture system onto a three-dimensional scaffold for construction of a tissue-engineered BM model. In combination with a novel approach for preparation of its in vivo injection, we have established the direct in vitro to in vivo transfer of a biomimetic BM niche. The novel methodological approaches presented here to study BMAds and the hematopoietic microenvironment, have far-reaching applications for improving the outcome of BM disease modeling, biomolecular and drug screening, as well as in regenerative medicine at large.

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Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

Olaia Maria Naveiras Torres-Quiroga, Josefine Catharina Pedersen Tratwal

The interest in bone marrow adiposity (BMA) has increased over the last decade due to its association with, and potential role, in a range of diseases (osteoporosis, diabetes, anorexia, cancer) as well as treatments (corticosteroid, radiation, chemotherapy, thiazolidinediones). However, to advance the field of BMA research, standardization of methods is desirable to increase comparability of study outcomes and foster collaboration. Therefore, at the 2017 annual BMA meeting, the International Bone Marrow Adiposity Society (BMAS) founded a working group to evaluate methodologies in BMA research. All BMAS members could volunteer to participate. The working group members, who are all active preclinical or clinical BMA researchers, searched the literature for articles investigating BMA and discussed the results during personal and telephone conferences. According to the consensus opinion, both based on the review of the literature and on expert opinion, we describe existing methodologies and discuss the challenges and future directions for (1) histomorphometry of bone marrow adipocytes, (2) ex vivo BMA imaging, (3) in vivo BMA imaging, (4) cell isolation, culture, differentiation and in vitro modulation of primary bone marrow adipocytes and bone marrow stromal cell precursors, (5) lineage tracing and in vivo BMA modulation, and (6) BMA biobanking. We identify as accepted standards in BMA research: manual histomorphometry and osmium tetroxide 3D contrast-enhanced μCT for ex vivo quantification, specific MRI sequences (WFI and H-MRS) for in vivo studies, and RT-qPCR with a minimal four gene panel or lipid-based assays for in vitro quantification of bone marrow adipogenesis. Emerging techniques are described which may soon come to complement or substitute these gold standards. Known confounding factors and minimal reporting standards are presented, and their use is encouraged to facilitate comparison across studies. In conclusion, specific BMA methodologies have been developed. However, important challenges remain. In particular, we advocate for the harmonization of methodologies, the precise reporting of known confounding factors, and the identification of methods to modulate BMA independently from other tissues. Wider use of existing animal models with impaired BMA production (e.g., Pfrt−/−, KitW/W−v) and development of specific BMA deletion models would be highly desirable for this purpose.

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MarrowQuantAcross Aging and Aplasia: A Digital Pathology Workflow for Quantification of Bone Marrow Compartments in Histological Sections

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