Bone marrow adipose tissue (BMAT), sometimes referred to as marrow adipose tissue (MAT), is a type of
fat deposit in
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
. It increases in states of low bone density -
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
,
anorexia nervosa
Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...
/
caloric restriction,
skeletal
unweighting such as that which occurs in
space travel, and anti-
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
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.
Anatomy
Bone marrow
adipocyte
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. I ...
s (BMAds)
originate from
mesenchymal stem cell (MSC) progenitors
In genealogy, the progenitor (rarer: primogenitor; german: Stammvater or ''Ahnherr'') is the – sometimes legendary – founder of a family, line of descent, clan or tribe, noble house, or ethnic group..
Ebenda''Ahnherr:''"Stammvater eines G ...
that also give rise to
osteoblast
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
s, among other cell types. Thus, it is thought that BMAT results from preferential
MSC differentiation into the
adipocyte
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. I ...
, 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
Vibration is a mechanical phenomenon whereby oscillations occur about an equilibrium point. The word comes from Latin ''vibrationem'' ("shaking, brandishing"). The oscillations may be periodic, such as the motion of a pendulum—or random, su ...
, 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
rodent
Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are n ...
s was published in 2014;
Now, exercise regulation of BMAT has been confirmed in a humansl 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
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-do ...
.
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
In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of ...
availability appears to be a factor in the ability of exercise to regulate BMAT.
Another exception occurs in
Lipodystrophy, a condition with reduced overall
adipose stores: exercise- induced
anabolism
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-do ...
is possible, even with minimal BMAT stores.
Relationships to other types of fat
BMAT has been reported to have qualities of both
white
White is the lightest color and is achromatic (having no hue). It is the color of objects such as snow, chalk, and milk, and is the opposite of black. White objects fully reflect and scatter all the visible wavelengths of light. White ...
and
brown
Brown is a color. It can be considered a composite color, but it is mainly a darker shade of orange. In the CMYK color model used in printing or painting, brown is usually made by combining the colors orange and black. In the RGB color model ...
fat. 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,.
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) and negative 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", regenerates cortisol, and recently has been tied to decreased bone formation Both types of
WAT substantially differ from
brown adipose tissue (BAT) as by a group of proteins that help BAT's
thermogenic
Thermogenic means tending to produce heat, and the term is commonly applied to drugs which increase heat through metabolic stimulation, or to microorganisms which create heat within organic waste. Approximately all enzymatic reaction in the huma ...
role. 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", and likely indicates a different fat phenotype. Recently, BMAT was noted to "produce a greater proportion of
adiponectin – an adipokine associated with improved metabolism – than
WAT", 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
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
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.
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
therapy in
postmenopausal osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone am ...
reduces BMAT. 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 and fat redistributes from subcutaneous to
ectopic sites such as
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
, muscle, and liver.
Aging
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
is associated with lower osteogenic and greater adipogenic biasing of MSC. This aging-related biasing of MSC away from osteoblast lineage may represent higher basal
PPARγ expression or decreased Wnt10b. Thus, bone fragility, osteoporosis, and osteoporotic fractures are thought to be linked to mechanisms which promote BMAT accumulation.
Maintenance of hematopoietic stem cells
BMAds secrete factors that promote HSC renewal in most bones.
Hematopoietic
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cell ...
cells (also known as blood cells) reside in the bone marrow along with BMAds. These hematopoietic cells are derived from
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...
s (HSC) which give rise to diverse cells: cells of the blood, immune system, as well as cells that break down bone (
osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
s). 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
Oncology is a branch of medicine that deals with the study, treatment, diagnosis and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's etymological origin is the Greek word ὄγκος (''ó ...
in order to improve therapy for multiple
hematologic cancers. As such cancers are often treated with
bone marrow transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
, there is interest in improving the renewal of HSC.
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
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cell ...
elements. Until recently, qualitative measurements of BMAT have relied on bone
histology
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures v ...
, which is subject to site
selection bias
Selection bias is the bias introduced by the selection of individuals, groups, or data for analysis in such a way that proper randomization is not achieved, thereby failing to ensure that the sample obtained is representative of the population int ...
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
The endosteum (plural endostea) is a thin vascular membrane of connective tissue that lines the inner surface of the bony tissue that forms the medullary cavity of long bones.
This endosteal surface is usually resorbed during long periods of ma ...
, milieu of cells, and secreted factors.
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. 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; nevertheless, this methodology continues to pose technical challenges 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, it is difficult to employ in laboratory animals.
Magnetic resonance imaging (MRI) provides BMAT assessment in the
vertebral skeleton in conjunction with
μCT-based marrow density measurements. A volumetric method to identify, quantify, and localize BMAT in rodent bone has been recently developed, requiring
osmium
Osmium (from Greek grc, ὀσμή, osme, smell, label=none) is a chemical element with the symbol Os and atomic number 76. It is a hard, brittle, bluish-white transition metal in the platinum group that is found as a trace element in alloys, ...
staining of bones and
μCT imaging, followed by advanced
image analysis
Image analysis or imagery analysis is the extraction of meaningful information from images; mainly from digital images by means of digital image processing techniques. Image analysis tasks can be as simple as reading bar coded tags or as soph ...
of osmium-bound lipid volume (in mm
3) relative to bone volume.
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
a 9.4T MRI scanner technique that allows localization and volumetric (3D) quantification that can be compared across experiments, as in.
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,.
The full extent of BMAT's impact on systemic metabolic homeostasis remains to be determined.
File:Demonstration of Method- Osmium-μCT with Advanced Image Processing.tif, alt=Demonstration of Osmium-μCT method with Advanced Image Processing, ''This figure demonstrates the use of the osmium- μCT method with advanced image processing to quantify BMAT. In this figure, running exercise is shown to suppress BMAT despite PPARγ agonist. Fat binder osmium is imaged via μCT (A ) in n =5 per group overlaid images. Quantification of osmium as BMAT/ bone volume in the whole femur is shown. a, significant due to Rosi. b, significant due to exercise. Rosi=rosiglizaone, CTL=control, E=exercise.''
File:MRI method copy.tif, ''This figure demonstrates the use of MRI imaging (9.4T scanner) along with advanced image processing to quantify BMAT. The images and graph demonstrate that BMAT is higher in obese compared with lean mice. B6 mice were fed HFD from age 4 wk until age 16 wk. BMAT was quantified by MRI. A) n=10 superimposed group average images are shown B) BMAT normalized to bone volume in each group.''
File:Marrow Adipose Tissue (typical quantity young mouse) .jpg, ''Representative distal femur histologic section of a 16-week-old healthy C57BL/6 mouse demonstrating a typical quantity of marrow adipocytes.''
File:Increased Marrow Adipose Tissue .jpg, ''Representative distal femur histologic section of a 16-week-old C57BL/6 mouse after 6 weeks of calorie restriction demonstrating an increased quantity of marrow adipocytes.''
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. 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.
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 groupshave published three position papers relating to nomenclature,
methodologies and biobanking for BMA research. 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)
* BMA2016 (Rotterdam, Netherlands)
* BMA2017 (Lausanne, Switzerland)
* BMA2018 (Lille, France)
BMA2019(Odense, Denmark)
* BMA2020 (virtual BMA meeting)
* BMA Summer School 2021 (virtual)
BMA2022(Athens, Greece)
American Society for Bone and Mineral Research
ASBMRhas published hundreds of presentations and articles on BMAT featured in the ASBMR annual meetings, Th
''Journal of Bone and Mineral Research'' ( ''JBMR''),
JBMRPlus and th
Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism
Endocrine Society
Endocrine societyfeatures many presentations and articles on BMAT.
References
Further reading
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{{DEFAULTSORT:Bone Marrow Adipose Tissue
Bone marrow
Bone fractures
Histology
Anatomy
Musculoskeletal system
Mesoderm