Bone marrow adipose tissue

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Bone marrow adipose tissue
Details
System Musculoskeletal (or locomotor)
Identifiers
Latin adipose ossium medulla
Anatomical terminology
Bone marrow adipocytes are derived from mesenchymal stem cell (MSC) differentiation. Marrow Adipocytes are derived from mesenchymal stem cell (MSC) differentiation. .tif
Bone marrow adipocytes are derived from mesenchymal stem cell (MSC) differentiation.

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, such as osteoporosis, [1] [2] anorexia nervosa/caloric restriction, [3] [4] skeletal unweighting such as that which occurs in space travel, [5] [6] and anti-diabetes therapies. [7] 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. [8]

Contents

Anatomy

Bone marrow adipocytes (BMAds) [9] originate from mesenchymal stem cell (MSC) progenitors that also give rise to osteoblasts, among other cell types. [10] Thus, it is thought that BMAT results from preferential MSC differentiation into the adipocyte, rather than osteoblast, lineage in the setting of osteoporosis. [11] Since BMAT is increased in the setting of obesity [12] [13] [14] and is suppressed by endurance exercise, [15] [12] [16] [17] or vibration, [18] it is likely that BMAT physiology, in the setting of mechanical input/exercise, approximates that of white adipose tissue (WAT).

Physiology

Exercise regulation

The first study to demonstrate exercise regulation of BMAT in rodents was published in 2014; [12] Now, exercise regulation of BMAT has been confirmed in a human, [19] adding clinical importance. Several studies demonstrated exercise reduction of BMAT which occurs along with an increase in bone quantity. [17] [15] [16] [20] 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. [16] 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. [4] [21] [20] Indeed, energy availability appears to be a factor in the ability of exercise to regulate BMAT. [4] Another exception occurs in lipodystrophy, a condition with reduced overall adipose stores: exercise- induced anabolism is possible, even with minimal BMAT stores. [22]

Relationships to other types of fat

BMAT has been reported to have qualities of both white and brown fat. [23] However, more-recent functional and -omics studies have shown that BMAT is a unique adipose depot that is molecularly and functionally distinct to WAT or BAT. [24] [25] [26] [27] Subcutaneous white fat contain excess energy, indicating a clear evolutionary advantage during times of scarcity. WAT is also the source of adipokines and inflammatory markers which have both positive (e.g., adiponectin) [28] and negative [29] effects on metabolic and cardiovascular endpoints. Visceral abdominal fat (VAT) is a distinct type of WAT that is "proportionally associated with negative metabolic and cardiovascular morbidity", [30] regenerates cortisol, [31] and recently has been tied to decreased bone formation [32] [33] Both types of WAT substantially differ from brown adipose tissue (BAT) as by a group of proteins that help BAT's thermogenic role. [34] BMAT, by its "specific marrow location, and its adipocyte origin from at least LepR+ marrow MSC is separated from non-bone fat storage by larger expression of bone transcription factors", [35] and likely indicates a different fat phenotype. [36] Recently, BMAT was noted to "produce a greater proportion of adiponectin – an adipokine associated with improved metabolism – than WAT", [37] suggesting an endocrine function for this depot, akin, but different, from that of WAT.

Impact on bone health

BMAT increases in states of bone fragility. BMAT is thought to result from preferential MSC differentiation into an adipocyte, rather than osteoblast lineage in osteoporosis [11] [20] based on the inverse relationship between bone and BMAT in bone-fragile osteoporotic states. An increase in BMAT is noted in osteoporosis clinical studies measured by MR spectroscopy. [38] [39] [40] Estrogen therapy in postmenopausal osteoporosis reduces BMAT. [41] Antiresorptive therapies like risedronate or zoledronate also decrease BMAT while increasing bone density, supporting an inverse relationship between bone quantity and BMAT. During aging, bone quantity declines [42] [43] and fat redistributes from subcutaneous to ectopic sites such as bone marrow, muscle, and liver. [44] Aging is associated with lower osteogenic and greater adipogenic biasing of MSC. [45] This aging-related biasing of MSC away from osteoblast lineage may represent higher basal PPARγ expression [46] or decreased Wnt10b. [47] [48] [49] Thus, bone fragility, osteoporosis, and osteoporotic fractures are thought to be linked to mechanisms which promote BMAT accumulation.[ citation needed ]

Maintenance of hematopoietic stem cells

BMAds secrete factors that promote HSC renewal in most bones. [50]

Hematopoietic cells (also known as blood cells) reside in the bone marrow along with BMAds. These hematopoietic cells are derived from hematopoietic stem cells (HSC) which give rise to diverse cells: cells of the blood, immune system, as well as cells that break down bone (osteoclasts). HSC renewal occurs in the marrow stem cell niche, a microenvironment that contains cells and secreted factors that promote appropriate renewal and differentiation of HSC. The study of the stem cell niche is relevant to the field of oncology in order to improve therapy for multiple hematologic cancers. As such cancers are often treated with bone marrow transplantation, there is interest in improving the renewal of HSC.[ citation needed ]

Measurement

In order to understand the physiology of BMAT, various analytic methods have been applied. BMAds are difficult to isolate and quantify because they are interspersed with bony and hematopoietic elements. Until recently, qualitative measurements of BMAT have relied on bone histology, [51] [52] which is subject to site selection bias and cannot adequately quantify the volume of fat in the marrow. Nevertheless, histological techniques and fixation make possible visualization of BMAT, quantification of BMAd size, and BMAT's association with the surrounding endosteum, milieu of cells, and secreted factors. [53] [54] [55]

Recent advances in cell surface and intracellular marker identification and single-cell analyses led to greater resolution and high-throughput ex-vivo quantification. Flow cytometric quantification can be used to purify adipocytes from the stromal vascular fraction of most fat depots. [56] Early research with such machinery cited adipocytes as too large and fragile for cytometer-based purification, rendering them susceptible to lysis; however, recent advances have been made to mitigate this; [57] nevertheless, this methodology continues to pose technical challenges [58] and is inaccessible to much of the research community.

To improve quantification of BMAT, novel imaging techniques have been developed as a means to visualize and quantify BMAT. Although proton magnetic resonance spectroscopy (1H-MRS) has been used with success to quantify vertebral BMAT in humans, [59] it is difficult to employ in laboratory animals. [60] Magnetic resonance imaging (MRI) provides BMAT assessment in the vertebral skeleton [61] in conjunction with μCT-based marrow density measurements. [62] A volumetric method to identify, quantify, and localize BMAT in rodent bone has been recently developed, requiring osmium staining of bones and μCT imaging, [63] followed by advanced image analysis of osmium-bound lipid volume (in mm3) relative to bone volume. [12] [16] [15] This technique provides reproducible quantification and visualization of BMAT, enabling the ability to consistently quantify changes in BMAT with diet, exercise, and agents that constrain precursor lineage allocation. Although the osmium method is quantitatively precise, osmium is toxic and cannot be compared across batched experiments. Recently, researchers developed and validated [16] a 9.4T MRI scanner technique that allows localization and volumetric (3D) quantification that can be compared across experiments, as in. [4]

Several studies have also analysed BMAT function in vivo using positron emission tomography - computed tomography (PET-CT) combined with the tracer 18F-Fluorodeoxyglucose (FDG). This allows glucose uptake, a measure of metabolic activity, to be quantified in living organisms, including humans. Two recent studies found that, unlike brown adipose tissue, BMAT does not increase glucose uptake in response to cold exposure, demonstrating that BMAT is functionally distinct from BAT. [24] [64] The full extent of BMAT's impact on systemic metabolic homeostasis remains to be determined.

Scientific societies

The International Bone Marrow Adiposity Society (BMAS)

Because of the increasing interest in BMAT from both researchers and clinicians, in 2018 The International Bone Marrow Adiposity Society (BMAS) was founded. [65] Work to build the society began in Lille, France in 2015, when the first International Meeting on Bone Marrow Adiposity (BMA2015) was held. The meeting was a great success and led to a second international meeting (BMA2016) in August 2016 held in Rotterdam, The Netherlands. Both meetings were a success in that they for the first time brought together scientists and physicians from different backgrounds (bone metabolism, cancer, obesity and diabetes) to share ideas and advance research into, and our understanding of, the patho/physiological role of BMAds.

Logo for The International Bone Marrow Adiposity Society BMAS Logo 2.tif
Logo for The International Bone Marrow Adiposity Society

This success led to a network of researchers discussing the formation of a new society, focusing on bone marrow adiposity (BMA). This network worked together in 2016–2017 to lay the foundations for this society, which was then discussed further during the third international meeting held in Lausanne, Switzerland in 2017 (BMA2017). The statues were then signed at the fourth international meeting, held in 2018 again in Lille (BMA2018). As discussed in the following section, there have since been three further international meetings, held in Odense, Denmark in 2019 (BMA2019), virtually in 2020 (BMA2020), and in Athens, Greece in 2022 (BMA2022). The first BMAS Summer School was held virtually in the summer of 2021.

Since its foundation, BMAS working groups have published three position papers relating to nomenclature, [9] methodologies [66] and biobanking for BMA research. [67] These working groups remain active, with other working groups also focussing on clinical and translational issues, public engagement, and young researchers (Next Generation BMAS)

BMAS meetings

  • BMA2015 (Lille, France) [68]
  • BMA2016 (Rotterdam, Netherlands) [69]
  • BMA2017 (Lausanne, Switzerland) [70]
  • BMA2018 (Lille, France) [71]
  • BMA2019 (Odense, Denmark)
  • BMA2020 (virtual BMA meeting) [72]
  • BMA Summer School 2021 (virtual) [73]
  • BMA2022 (Athens, Greece)

American Society for Bone and Mineral Research

ASBMR has published hundreds of presentations and articles on BMAT featured in the ASBMR annual meetings, The Journal of Bone and Mineral Research ( JBMR), JBMRPlus, and the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism.

Endocrine Society

Endocrine society features many presentations and articles on BMAT.

Related Research Articles

<span class="mw-page-title-main">Bone</span> Rigid organs that constitute part of the endoskeleton of vertebrates

A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and enable mobility. Bones come in a variety of shapes and sizes and have complex internal and external structures. They are lightweight yet strong and hard and serve multiple functions.

<span class="mw-page-title-main">Osteoporosis</span> Skeletal disorder

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk.

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin, also known as obese protein, is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Brown adipose tissue</span> Type of adipose tissue

Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue. Brown adipose tissue is found in almost all mammals.

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Resistin</span> Mammalian protein found in Homo sapiens

Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.

<span class="mw-page-title-main">Bone resorption</span> Breakdown of bone tissue to be absorbed into the blood

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<span class="mw-page-title-main">Sclerostin</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Osteocalcin</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Perilipin-1</span> Protein in humans

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<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Adipogenesis</span>

Adipogenesis is the formation of adipocytes from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as lipoblasts or preadipocytes which lose the potential to differentiate to other types of cells such as chondrocytes, myocytes, and osteoblasts. Terminal differentiation is that preadipocytes differentiate into mature adipocytes. Adipocytes can arise either from preadipocytes resident in adipose tissue, or from bone-marrow derived progenitor cells that migrate to adipose tissue.

<span class="mw-page-title-main">Mesenchymal stem cell</span> Multipotent, non-hematopoietic adult stem cells present in multiple tissues

Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes.

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<span class="mw-page-title-main">SRT-3025</span> Organic compound, experimental pharmaceuticum

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References

Creative Commons by small.svg  This article incorporates text by Gabriel M. Pagnotti and Maya Styner available under the CC BY 4.0 license.

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