Table Of ContentAdipocyte2:1,50–54;January/February/March2013;G2013LandesBioscience
The transcription factors myeloid elf-1-like factor (MEF) and distal-less
homeobox 5 (Dlx5) inversely regulate the differentiation of osteoblasts
and adipocytes in bone marrow
Kyunghwa Baek1 and Jeong-Hwa Baek2,*
1DepartmentofPharmacology;CollegeofDentistry;Gangneung-WonjuNationalUniversity;Gangwondo,Korea;2DepartmentofMolecularGenetics;
SchoolofDentistryandDentalResearchInstitute;SeoulNationalUniversity;Seoul,Korea
In bone marrow, the differentiation of 20–30% of total bMSCs are multipotent1
osteoblastsandadipocytesisrecip- and the remainder of the population is a
rocally regulated. This inverse regulation mixture of bi-potential and uni-potential
occurs mainly through complex signaling MSCs.2 Two of the uni-potent popula-
Keywords: adipocyte, osteoblast, myeloid
crosstalk between transcriptional factors tions of bMSCs are cells that are commit-
elf-1-like factor, distal-less homeobox 5,
such as peroxisome proliferator-activated ted to either osteoblastic or adipocytic
bone marrow mesenchymal stem cells
receptor-c (PPARc) and runt-related lineages.3
Abbreviations: BMP2, bone transcription factor 2 (Runx2). This In several in vivo studies, a decrease in
morphogenetic protein-2; bMSCs, bone commentary addresses the role of mye- bonemasshasbeenshowntobeassociated
marrow mesenchymal stem cells; C/ loidelf-1likefactor(MEF)anddistal-less with an increase in the adipocyte cell
EBPa, CCAAT/enhancer-binding protein homeobox 5 (Dlx5) in the lineage populationinthebonemarrow,suggesting
a; CREB, cAMP response element commitment of bone marrow mesenchy- an inverse relationship between adipocyte
binding protein; Dlx5, distal-less mal stem cells into adipocytes and differentiation and osteoblast differenti-
homeobox 5; HD, homeodomain; osteoblasts, respectively. MEF suppresses ation.4 Extracellular signals that promote
MEF, myeloid elf-1 like factor; osteoblastogenesis by preventing Runx2 commitment of bMSCs to the osteoblast
miRNA, microRNA; PPARc, peroxisome from binding to the promoters of target lineage actively suppress mechanisms that
proliferator-activated receptor-c; genes and enhancing adipogenesis via induceadipocytelineagecommitmentand
Runx2, runt-related transcription factor 2 transactivation of PPARc expression. vice versa. There exist various regulation
Conversely, Dlx5 enhances osteoblasto- mechanisms involved in this lineage com-
Submitted: 06/25/12 genesis through upregulation of the mitment. At transcriptional regulation
Revised: 08/28/12 expression of Runx2 and osteoblast level, transcription factors including mye-
marker genes while suppressing adipo- loid elf-1 like factor (MEF),5,6 distal-less
Accepted: 08/29/12
genesis through the downregulation of homeobox 5 (Dlx5),5-8 Wnt/β-catenin,9
http://dx.doi.org/10.4161/adip.22019 PPARc expression by sequestering the meshless homeobox 2,10 secreted frizzled-
*Correspondenceto:Jeong-HwaBaek; cAMP response element binding protein related protein 111 and delta-like1/preadi-
Email:[email protected] and CCAAT/enhancer-binding protein pocyte factor 112 are now known to
a.Studiesdesignedtoexaminetheeffects reciprocally regulate bone marrow adipo-
Commentaryto:BaekK,ChoJY,HwangHR, ofphysiologicalandpathologicsignalson genesisandosteogenesismainlyviamodu-
KwonA,LeeHL,ParkHJ,etal.MyeloidElf-1-like
the expression of MEF and Dlx5 will lation of complex crosstalk pathway
factorstimulatesadipogenicdifferentiation
provide further insight to the function of between master switch genes, peroxisome
throughtheinductionofperoxisomeprolifera-
tor-activatedreceptorcexpressioninbone these transcription factors in vivo. proliferator-activated receptor-c (PPARc)
marrow.JCellPhysiol2012;227:3603–12;PMID: and runt-related transcription factor 2
22307523;http://dx.doi.org/10.1002/jcp.24064 (Runx2). PPARc, a ligand-activated tran-
and
In bone marrow, osteoblasts and adipo- scription factor, is a master regulator of
LeeHL,WooKM,RyooHM,BaekJH.Distal-less
cytes arise from a common progenitor: adipocyte differentiation. PPARc knock-
homeobox5inhibitsadipogenicdifferentiation
throughthedown-regulationofperoxisome bone marrow mesenchymal stem cells out mice failed to generate adipose tissue,
proliferator-activatedreceptorcexpression.JCell (bMSCs). Even though bMSCs are con- even when fed a high fat diet.13 PPARc
Physiol2012;228:87–98;PMID:22553076;http:// sidered multipotent, clonal analysis of formsheterodimers with retinoidX recep-
dx.doi.org/10.1002/jcp.24106
bMSC populations has revealed that only tors and regulates the transcription of
50 Adipocyte Volume2Issue1
COMMENTARY
various adipogenic genes. Runx2 is a six (Ets) family transcription factors.24 All of the Distal-less HD protein family and
master transcription factor of osteoblast Ets family members encode unique tran- hasbeenimplicatedinthecommitmentof
differentiation and bone mineralization.14 scriptional regulators that have a highly mesenchymalprogenitorstotheosteoblast
Targeted disruption of Runx2 induced a conserved DNA binding domain. Ets lineagethroughtheupregulationofRunx2
complete lack of bone formation due to family transcription factors have been and Osterix expression.7 Dlx5-deficient
maturational arrest of osteoblasts.15 implicated in various biological processes, mice showed defects in bone formation,26
Interaction between PPARc and Runx2 including hematopoiesis,innate immunity and expression of Dlx5 is rapidly induced
regulates the reciprocal differentiation and extracellular matrix mineralization. by BMP2.27 Dlx5 also upregulates the
pathways that control commitment of Kim et al. previously demonstrated that expression of alkaline phosphatase and
bMSCs to osteoblast and adipocyte MEF expression is highest during early osteocalcinthroughdirectbindingtotheir
lineages. PPARc negatively regulates stro- differentiation of MC3T3-E1 osteoblasts respective gene promoters.28 We recently
mal cell plasticity by suppressing Runx2 andthatitsexpressionlevelisdecreasedby demonstrated that Dlx5 exerts an anti-
and osteoblast-like biosynthetic activity, bone morphogenetic protein-2 (BMP2), adipogenic effect through downregulation
while promoting adipocyte differenti- one of the strongest inducers of osteoblast of PPARc expression and that adipogenic
ation.16 Heterozygous PPARc-deficient differentiation.6MEFwasshowntoforma stimulirapidlydownregulatetheexpression
mice exhibited a high bone mass with complex with Runx2 and prevent it from levels of Dlx5.8 Overexpression of Dlx5
increased osteoblastogenesis and decreased bindingtothecis-actingelementOSE2in suppressedtheadipogenicdifferentiationof
marrow fat,17 while osteoblast-targeted the osteocalcin promoter, which in turn, bMSCs and 3T3-L1 pre-adipocytes while
overexpression of PPARc decreased bone suppressed BMP2-induced osteocalcin knockdown of Dlx5 promoted adipogenic
mass in male mice and accelerated ova- expression in MC3T3-E1 osteoblasts. differentiation. Overexpression of PPARc
riectomy-induced bone loss in female Osteoblast-specific MEF transgenic mice or treatment with rosiglitazone, a PPARc
mice.18 Regulations of osteoblast/adipo- (Col1a1-MEF TG mice) exhibited ligand, rescued adipogenic differentiation
cyte lineage commitment at the post- decreased bone mass and higher marrow of 3T3-L1 cells overexpressing Dlx5, in-
transcriptional level such as microRNA fat accumulation in long bones than their dicating that downregulation of PPARc
(miRNA) control have been recently wild-type counterparts.25 expression was a major anti-adipogenic
explored. miRNAs, are endogenous non- Recently,wedemonstratedthatMEFis mechanism.Dlx5suppressesPPARcexpres-
coding RNAs, 22–25 nucleotides in apositiveregulatorofadipocytedifferenti- sion by sequestering the cAMP response
length, which bind to complementary ation.5 bMSCs derived from Col1a1-MEF element binding protein (CREB) and C/
sequences on target mRNA transcripts TG mice showed a higher adipogenic EBPa, transcriptional activators of PPARc,
and post-transcriptionally regulate various differentiation potential than those from ratherthanbydirectbindingtothePPARc
biological processes.19miRNAs canstimu- wild-type mice. Adipogenic stimuli promoter.
late or suppress adipocyte differentiation increased MEF expression, and knock- These reports indicate that in the bone
and also regulate the lineage commitment down of MEF suppressed adipogenic marrow, MEF and Dlx5 play a role as
ofbMSC.20FewmiRNAtargetshavebeen differentiation of 3T3-L1 pre-adipocytes. lineagedeterminantsforthedifferentiation
experimentally verified in adipocytes. But Forced expression of MEF in MC3T3-E1 of adipocytes and osteoblasts, respectively.
recently it has been demonstrated that osteoblasts induced them to secrete higher As described above, extracellular osteo-
both miR-27 and miR-519d suppress levels of 15d-PGJ , a strong endogenous genicsignals,suchasthosestemmingfrom
2
adipogenesis by targeting PPAR family PPARc ligand, thereby creating a micro- BMP2-activated signaling, increased the
members21,22 whereas miR-204/211 inhi- environment in the marrow that favors expression of Dlx5, an osteogenic tran-
bits osteogenesis and promotes adipogen- adipogenesis. Furthermore, MEF overex- scription factor, but decreased the expres-
esis of mesenchymal progenitor cells and pression upregulated the expression of sion of MEF, an adipogenic transcription
bMSCs by targeting Runx2.23 adipogenic marker genes, including factor.Conversely,extracellularadipogenic
In the next two sections, we will focus PPARc and CCAAT/enhancer-binding signals increased the expression of MEF
on the regulation of marrow adiposity at protein a (C/EBPa), and increased lipid but suppressed the expression of Dlx5.
transcriptional level and especially on two droplet accumulation in MC3T3-E1 Thesefindingsfurthersupporttheconcept
transcription factors, MEF and Dlx5, osteoblasts and 3T3-L1 pre-adipocytes. that specific extracellular cues dictate the
which are recently demonstrated to inver- PPARc was shown to be a target gene of commitment and subsequent differenti-
sely regulate osteoblast/adipocyte differ- MEF, which directly binds to the PPARc ation of bMSCs toward one lineage via
entiationbyactingupstreamofRunx2and promoter and enhances its transcription. suppression of the expression or functions
PPARc.11,12 of transcription factors in one lineage and
Distal-Less Homeobox 5 (Dlx5) induction of transcription factors in the
Myeloid Elf-1 Like Factor (MEF) other lineage. Another common theme of
Boneformationisorchestratedbymultiple these transcription factor studies was that
MEFwasoriginallyisolatedfromahuman homeodomain (HD) proteins, which are MEF and Dlx5 act as transcriptional
megakaryocytic leukemia cell line and sub-grouped based on their sequences and activators of PPARc and Runx2, respect-
belongs to the Elf-1/E74 group of E-20 their homeobox motifs. Dlx5isa member ively,bydirectlybindingtotheirpromoter
www.landesbioscience.com Adipocyte 51
regions, whereas they negatively regulate new function for marrow adipocytes as potentially positive role for adipocytes in
the function of Runx2 and the expression modulators of adjacent cell activity has bone formation. When new bone forma-
of PPARc, respectively, through protein- been suggested. Endosteal adipocytes may tion was triggered in skeletal muscle by
protein interactions. Figure1 summarizes suppress osteoblast proliferation and dif- BMP2 injection, accumulation of brown-
how Dlx5, whose expression is increased ferentiation by releasing adipokines, such like adipocytes was observed transiently,
by osteogenic signals, or MEF, whose as leptin and adiponectin, and/or by followed by heterotopic bone formation,
expression is increased by adipogenic making direct contact in the bone mar- suggestingthatbrown-likeadipocytesmay
signaling, regulate Runx2 and PPARc row.29,30,31 Furthermore, it has been stimulate bone formation.33 Considering
expression and function and subsequently demonstrated that uni-potent bMSCs that the primary role of brown fat is
induce osteogenic and adipogenic differ- of the adipocyte lineage also negatively thermogenesis, brown-like adipocytes may
entiation of bMSCs. regulate osteogenic differentiation of provide energy to the neighboring bone-
Classically, bone marrow fat has been neighboring bMSCs via the secretion forming microenvironment. Recently, it
considered to be primarily a filler for the of frizzled-related protein 1, an inhibitor was demonstrated that bone marrow fat
void vacated by bone and was believed to of the canonical Wnt pathway.32 In expresses genetic markers of brown adipo-
be metabolically inert. However, in light contrast to reports showing an anti- cytes, including Prdm16 (PR domain
of several studies demonstrating the osteogenic role for bone marrow adipo- containing 16) and Ppargc1a (peroxisome
dynamic features of bone marrow fat, a cytes, another report has demonstrated a proliferative activated receptor, gamma,
Figure1.Marrowfataccumulationiscloselyrelatedtoboneformation.Osteoblastsandadipocytesarederivedfromcommonmultipotential
mesenchymalstemcells.ExtracellularsignalsthatpromotethedifferentiationofbMSCsintoadipocytesinduceMEFexpression.MEFthenenhances
adipogenesisviatransactivationofPPARcexpressionandsuppressesosteoblastogenesisbypreventingRunx2frombindingtothepromoteroftarget
genessuchasosteocalcin.ExtracellularsignalsthatpromotethedifferentiationofbMSCsintoosteoblastsinduceDlx5expression.Dlx5thenenhances
osteoblastogenesisthroughtheupregulationofRunx2andosteoblastmarkergeneexpression,andsuppressesadipogenesisthroughthe
downregulationofPPARcexpressionbysequesteringCREBandC/EBPa.
52 Adipocyte Volume2Issue1
coactivator 1 a), at levels characteristic of ofbonemarrowfatandmarrowadiposity. sympatheticnervoussystemactivationare
brown adipose tissue and that the expres- Investigations into the physiological sig- known to increase bone marrow fat
sion levels of brown adipocyte marker nificance of bone marrow infiltration with deposition. Further research regarding
genes decrease in the bones of aged and adipocytes, particularly with respect to the effects of these risk factors on the
diabetic mice.34 Considering that aging growth/aging,andtheexactrolesoflocally expressionofMEFandDlx5isnecessary.
and diabetes are representative risk factors secreted hormones and adipokines will In addition, further investigation into the
for decreased bone formation and permit a better understanding of the natureofadipocytes,brown-likeorwhite,
increased bone fat,4 the question arises as physiological and pathologic roles of bone whose levels are increased in bone
towhetheraginganddiabetesinducethese marrow fat. marrow by aging, obesity, diabetes and
changes in the characteristics of bone In conclusion, we present here recent disuse, would provide insight into the
marrow adipocytes. Whether the tran- evidence demonstrating that the tran- function of bone fat under these osteo-
scription factors for white adipogenesis scription factors MEF and Dlx5 inversely penic conditions.
would also positively regulate the brown regulate osteoblast and adipocyte differ-
adipogenesisisyettobeknown.Thatis,it entiation upstream of Runx2 and Acknowledgments
is uncertain how MEF or Dlx5 effect on PPARc in bMSCs. The physiological This work was supported by the National
the lineage commitment of bMSCs into and molecular changes that occur in ResearchFoundationofKorea(NRF)grant
brown adipocytes. Further research is association with aging, diet restriction or fundedbytheKoreangovernment(MEST)
warranted to determine the exact nature high fat diets, diabetes, disuse and/or (2009-0068779,2011-0016548).
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