Osteoblast differentiation (Homo sapiens)

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1-3Endochondral ossificationDeletion of OSXSOX9+ cells arebipontentialDeletion of beta-catenin geneMesenchymal progenitor/Mesenchymal stem cellSMOJAG2SMAD1IHHGLI2LRP5NOTCH1STAT1PRKCDDLL1LRP6HEY1FGFR1CTNNB1RBPJHES2BMPR1AGLI3JAG1HES3BMP4GeneProductPTCH1MYOD1BMP2Osteo-chondro progenitorPreosteoblastChondroblastPerichondral cellChondrocyteHypertrophic chondrocyteOsteoblastIntramembranousSOX9+RUNX2+RUNX2+OSX+DLL3DLL4NOTCH2NOTCH3NOTCH4HES6HEY2BMPR1BBMPR2SMAD5SMAD9SMAD1PSMAD5PSMAD9PPPPSMAD4SMAD1PPSMAD4SMAD4SMAD5PPSMAD9PPFGFR3FGFR2FGFR4OsteoblastAdipogenic lineageMyogenic lineagePPARGRUNX2SOX9OsteocyteCalvarian bones, claviclesAxial skeleton, extremitiesFZD9FZD6FZD7FZD4FZD1FZD8FZD10FZD2FZD3FZD5FZD9FZD6FZD7FZD4FZD1FZD8FZD10FZD2FZD3FZD5WNT16WNT3AWNT7AWNT10BWNT6WNT9BWNT11WNT7BWNT10AWNT2BWNT5BWNT8AWNT1WNT5AWNT9AWNT3WNT4WNT2WNT8BPRKCIPRKDCPIK3C2APIK3R6PRKCEPIK3R3PIK3R4PIK3R5PRKCHPRKCGPIK3C3PRKCZPIK3CBPIK3CAPRKCAPRKCBPRKCDPIK3CDPRKCQPIK3C2BPIK3C2GPIK3CGPIK3R2PRKD1PIK3R1OMIM:101600Pfeiffer SyndromeOMIM:164745Omodysplasia 2OMIM:612247Crouzon Syndrome With Acanthosis NigricansOMIM:146510Pallister-Hall SyndromeOMIM:114290Campomelic DysplasiaOMIM:101200Apert SyndromeOMIM:616482Achondroplasia, Severe, With Developmental Delay And Acanthosis NigricansOMIM:156510Metaphyseal Dysplasia With Maxillary Hypoplasia With Or Without BrachydactylyOMIM:609441Acromesomelic Dysplasia, Demirhan TypeOMIM:149730Lacrimoauriculodentodigital SyndromeOMIM:616028Adams-Oliver Syndrome 5OMIM:102500Hajdu-Cheney SyndromeOMIM:273395Tetraamelia Syndrome 1OMIM:139210Myhre SyndromeOMIM:123790Beare-Stevenson Cutis Gyrata SyndromeOMIM:612918Congenital Lipomatous Overgrowth, Vascular Malformations, And Epidermal NeviOMIM:174700Polydactyly, Preaxial IvOMIM:614814Adams-Oliver Syndrome 3OMIM:166710OsteoporosisOMIM:175700Greig Cephalopolysyndactyly SyndromeOMIM:187600Thanatophoric Dysplasia, Type IOMIM:123500Crouzon SyndromeOMIM:228930Fibular Aplasia Or Hypoplasia, Femoral Bowing And Poly-, Syn-, And OligodactylyOMIM:180700Robinow Syndrome, Autosomal Dominant 1OMIM:607778Acrocapitofemoral DysplasiaOMIM:144750Endosteal Hyperostosis, Autosomal DominantOMIM:277300Spondylocostal Dysostosis 1, Autosomal RecessiveOMIM:146000HypochondroplasiaOMIM:185900Chromosome 2q35 Duplication SyndromeOMIM:101600Pfeiffer SyndromeOMIM:614592Bent Bone Dysplasia SyndromeOMIM:112500Brachydactyly, Type A1OMIM:602849Muenke SyndromeOMIM:166250Osteoglophonic DysplasiaOMIM:100800AchondroplasiaOMIM:119600Cleidocranial DysplasiaOMIM:102510Acropectorovertebral DysplasiaOMIM:276820Ulna And Fibula, Absence Of, With Severe Limb DeficiencyOMIM:615220Osteogenesis Imperfecta, Type XVOMIM:112600Brachydactyly, Type A2OMIM:225300Split-Hand/foot Malformation 6OMIM:112600Brachydactyly, Type A2OMIM:164745Omodysplasia 2OMIM:616589Adams-Oliver Syndrome 6OMIM:610474Camptodactyly, Tall Stature, And Hearing Loss SyndromeOMIM:259770Osteoporosis-Pseudoglioma SyndromeOMIM:187601Thanatophoric Dysplasia, Type IIOMIM:615465Hartsfield SyndromeFGF1FGF10FGF6FGF2FGF4FGF3FGF7FGF8FGF9FGF5FGF18OMIM:612961Multiple Synostoses Syndrome 3MAPK9MAPK3MAPK13MAPK6MAPK10MAPK4MAPK1MAPK8MAPK11MAPK12MAPK7MAPK14WNT16WNT3AWNT7AWNT10BWNT6WNT9BWNT11WNT7BWNT10AWNT2BWNT5BWNT8AWNT1WNT5AWNT9AWNT3WNT4WNT2WNT8BOMIM:273395Tetraamelia Syndrome 1OMIM:228930Fibular Aplasia Or Hypoplasia, Femoral Bowing And Poly-, Syn-, And OligodactylyOMIM:180700Robinow Syndrome, Autosomal Dominant 1OMIM:102510Acropectorovertebral DysplasiaOMIM:276820Ulna And Fibula, Absence Of, With Severe Limb DeficiencyOMIM:615220Osteogenesis Imperfecta, Type XVOMIM:225300Split-Hand/foot Malformation 6


Description

Taken from:

Building stronger bones: molecular regulation of the osteoblast lineage by Fanxin Long [1]. Osteoblast differentiation at a glance, Arkady Rutkovskiy, Kåre-Olav Stensløkken, Ingvar Jarle Vaage [2]. Development of the endochondral skeleton by Fanxin Long, David Ornitz [3].

Mesenchymal stem cells can give rise to 4 lineages by expressing corresponding transcriptional regulators: PPARg for adipogenic, MyoD for myogenic, Runx2 for osteoblastic, and Sox9 for chondrocytic lineages. In intramembranous ossification (osteogenesis in the scull and clavicles), preosteoblasts stem directly from mesenchymal stem cells, while in endochondral (osteogenesis of the axial skeleton and the limbs) a common osteo-chondro progenitor gives rise to both cell types.

Extracellular signals regulating osteoblast differentiation: Model is based on studies of the mouse limb skeleton. Osteoblasts differentiate from mesenchymal progenitors (MP) through distinct developmental stages marked by expression of key transcription factors including SOX9, RUNX2, and OSX. Mature osteoblasts (OB) can further differentiate to osteocytes (OCY) or bone lining cells (not depicted) or undergo apoptosis (not depicted).

Indian hedgehog (IHH) signaling is required for osteoblast differentiation during endochondral bone development. IHH binding to the receptor Patched homolog 1 (PTCH1) activates signaling through Smoothened (SMO), thereby inhibiting the generation of the proteolytically cleaved GLI3 repressor (GLI3R) and promoting the generation of the full-length GLI2 activator (GLI2A). Whereas derepression of GLI3R is sufficient to generate RUNX2+ cells, both derepression of GLI3R and activation of GLI2A are necessary for progression to the RUNX2+OSX+ stage. NOTCH signaling inhibits osteoblast differentiation. Following binding to their ligands, Jagged (JAG) or Delta-like (DLL), Notch receptors are proteolytically cleaved by the g-secretase complex, leading to release of the Notch intracellular domain (NICD) from the plasma membrane. NICD interacts with RBPJk and together they activate downstream target genes, including HES (Hairy and Enhancer of Split) and HEY (HES-related with YRPW motif) family transcription factors, ultimately leading to inhibition of osteoblast differentiation, seemingly at a stage before OSX activation.

WNT signaling promotes osteoblast differentiation. During b-catenin-dependent WNT signaling, b-catenin is stabilized following binding of WNT to its receptors Frizzled (FZD) and lipoprotein receptor-related protein 5 (LRP5) or LRP6, leading to the transcription of b-catenin target genes and ultimately stimulating progression from the RUNX2+ stage to the RUNX2+OSX+ stage, and from RUNX2+OSX+ cells to mature osteoblasts. WNTcan also signal independently of LRP5/6 and b-catenin through protein kinase Cd (PKCd), promoting progression to the RUNX2+OSX+ stage through an unknown mechanism.

Bone morphogenetic protein (BMP) signaling stimulates osteoblast differentiation and function. Binding of BMP2 or BMP4 to their receptors results in phosphorylation of SMAD1, SMAD5, or SMAD8. These can then form a complex with their partner, SMAD4, and enter the nucleus to regulate gene expression, ultimately promoting the transition to RUNX2+OSX+ cells and enhancing the function of mature osteoblasts; however, a direct role for SMAD signaling in osteoblast differentiation remains to be shown.

Fibroblast growth factor (FGF) signaling has diverse roles in osteoblast lineage cells. FGFs function by binding to cell surface Tyr kinase FGF receptors (FGFR1–FGFR4 in humans and mice), leading to the activation of multiple signaling modules. FGF signaling regulates preosteoblast proliferation and osteoblast differentiation, as well as the function of mature osteoblasts. However, the precise stages at which FGFs regulate proliferation and differentiation, and the intracellular signaling cascades responsible for each function, remain to be elucidated. BMPR, BMP receptor; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; STAT1, signal transducer and activator of transcription 1.

Linked with a dotted arrow to the GeneProduct nodes are diseases caused by mutation in the respective gene.

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Ontology Terms

 

Bibliography

  1. Long F, Ornitz DM; ''Development of the endochondral skeleton.''; Cold Spring Harb Perspect Biol, 2013 PubMed Europe PMC Scholia
  2. Long F; ''Building strong bones: molecular regulation of the osteoblast lineage.''; Nat Rev Mol Cell Biol, 2011 PubMed Europe PMC Scholia
  3. Rutkovskiy A, Stensløkken KO, Vaage IJ; ''Osteoblast Differentiation at a Glance.''; Med Sci Monit Basic Res, 2016 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
112157view18:04, 29 September 2020Khanspersfixed ptm states, removed extraneous empty gene
111734view17:22, 3 September 2020KhanspersOntology Term : 'Hedgehog signaling pathway' added !
111733view17:21, 3 September 2020KhanspersOntology Term : 'fibroblast growth factor signaling pathway' added !
111732view17:21, 3 September 2020KhanspersOntology Term : 'Wnt signaling pathway' added !
111731view17:20, 3 September 2020KhanspersOntology Term : 'osteoblast' added !
110652view10:20, 25 May 2020RleeFixed an unconnected line.
108819view05:10, 31 January 2020RleeModified description
108818view05:07, 31 January 2020RleeModified description
108817view05:04, 31 January 2020RleeAdded a box around FZD and LRP to indicate that CTNNB1 is only expressed when both FZD and LRP are activated
108816view05:00, 31 January 2020RleeNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
BMP2GeneProductENSG00000125845 (Ensembl)
BMP4GeneProductENSG00000125378 (Ensembl)
BMPR1AGeneProductENSG00000107779 (Ensembl)
BMPR1BGeneProductENSG00000138696 (Ensembl)
BMPR2GeneProductENSG00000204217 (Ensembl)
CTNNB1GeneProductENSG00000168036 (Ensembl)
DLL1GeneProductENSG00000198719 (Ensembl)
DLL3GeneProductENSG00000090932 (Ensembl)
DLL4GeneProductENSG00000128917 (Ensembl)
FGF10GeneProductENSG00000070193 (Ensembl)
FGF18GeneProductENSG00000156427 (Ensembl)
FGF1GeneProductENSG00000113578 (Ensembl)
FGF2GeneProductENSG00000138685 (Ensembl)
FGF3GeneProductENSG00000186895 (Ensembl)
FGF4GeneProductENSG00000075388 (Ensembl)
FGF5GeneProductENSG00000138675 (Ensembl)
FGF6GeneProductENSG00000111241 (Ensembl)
FGF7GeneProductENSG00000140285 (Ensembl)
FGF8GeneProductENSG00000107831 (Ensembl)
FGF9GeneProductENSG00000102678 (Ensembl)
FGFR1GeneProductENSG00000077782 (Ensembl)
FGFR2GeneProductENSG00000066468 (Ensembl)
FGFR3GeneProductENSG00000068078 (Ensembl)
FGFR4GeneProductENSG00000160867 (Ensembl)
FZD10GeneProductENSG00000111432 (Ensembl)
FZD1GeneProductENSG00000157240 (Ensembl)
FZD2GeneProductENSG00000180340 (Ensembl)
FZD3GeneProductENSG00000104290 (Ensembl)
FZD4GeneProductENSG00000174804 (Ensembl)
FZD5GeneProductENSG00000163251 (Ensembl)
FZD6GeneProductENSG00000164930 (Ensembl)
FZD7GeneProductENSG00000155760 (Ensembl)
FZD8GeneProductENSG00000177283 (Ensembl)
FZD9GeneProductENSG00000188763 (Ensembl)
GLI2GeneProductENSG00000074047 (Ensembl)
GLI3GeneProductENSG00000106571 (Ensembl)
GeneProductGeneProduct
HES2GeneProductENSG00000069812 (Ensembl)
HES3GeneProductENSG00000173673 (Ensembl)
HES6GeneProductENSG00000144485 (Ensembl)
HEY1GeneProductENSG00000164683 (Ensembl)
HEY2GeneProductENSG00000135547 (Ensembl)
IHHGeneProductENSG00000163501 (Ensembl)
JAG1GeneProductENSG00000101384 (Ensembl)
JAG2GeneProductENSG00000184916 (Ensembl)
LRP5GeneProductENSG00000162337 (Ensembl)
LRP6GeneProductENSG00000070018 (Ensembl)
MAPK10GeneProductENSG00000109339 (Ensembl)
MAPK11GeneProductENSG00000185386 (Ensembl)
MAPK12GeneProductENSG00000188130 (Ensembl)
MAPK13GeneProductENSG00000156711 (Ensembl)
MAPK14GeneProductENSG00000112062 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MAPK3GeneProductENSG00000102882 (Ensembl)
MAPK4GeneProductENSG00000141639 (Ensembl)
MAPK6GeneProductENSG00000069956 (Ensembl)
MAPK7GeneProductENSG00000166484 (Ensembl)
MAPK8GeneProductENSG00000107643 (Ensembl)
MAPK9GeneProductENSG00000050748 (Ensembl)
MYOD1GeneProductENSG00000129152 (Ensembl)
NOTCH1GeneProductENSG00000148400 (Ensembl)
NOTCH2GeneProductENSG00000134250 (Ensembl)
NOTCH3GeneProductENSG00000074181 (Ensembl)
NOTCH4GeneProductENSG00000204301 (Ensembl)
PIK3C2AGeneProductENSG00000011405 (Ensembl)
PIK3C2BGeneProductENSG00000133056 (Ensembl)
PIK3C2GGeneProductENSG00000139144 (Ensembl)
PIK3C3GeneProductENSG00000078142 (Ensembl)
PIK3CAGeneProductENSG00000121879 (Ensembl)
PIK3CBGeneProductENSG00000051382 (Ensembl)
PIK3CDGeneProductENSG00000171608 (Ensembl)
PIK3CGGeneProductENSG00000105851 (Ensembl)
PIK3R1GeneProductENSG00000145675 (Ensembl)
PIK3R2GeneProductENSG00000105647 (Ensembl)
PIK3R3GeneProductENSG00000117461 (Ensembl)
PIK3R4GeneProductENSG00000196455 (Ensembl)
PIK3R5GeneProductENSG00000141506 (Ensembl)
PIK3R6GeneProductENSG00000276231 (Ensembl)
PPARGGeneProductENSG00000132170 (Ensembl)
PRKCAGeneProductENSG00000154229 (Ensembl)
PRKCBGeneProductENSG00000166501 (Ensembl)
PRKCDGeneProductENSG00000163932 (Ensembl)
PRKCEGeneProductENSG00000171132 (Ensembl)
PRKCGGeneProductENSG00000126583 (Ensembl)
PRKCHGeneProductENSG00000027075 (Ensembl)
PRKCIGeneProductENSG00000163558 (Ensembl)
PRKCQGeneProductENSG00000065675 (Ensembl)
PRKCZGeneProductENSG00000067606 (Ensembl)
PRKD1GeneProductENSG00000184304 (Ensembl)
PRKDCGeneProductENSG00000253729 (Ensembl)
PTCH1GeneProductENSG00000185920 (Ensembl)
RBPJGeneProductENSG00000168214 (Ensembl)
RUNX2GeneProductENSG00000124813 (Ensembl)
SMAD1GeneProductENSG00000170365 (Ensembl)
SMAD4GeneProductENSG00000141646 (Ensembl)
SMAD5GeneProductENSG00000113658 (Ensembl)
SMAD9GeneProductENSG00000120693 (Ensembl)
SMOGeneProductENSG00000128602 (Ensembl)
SOX9GeneProductENSG00000125398 (Ensembl)
STAT1GeneProductENSG00000115415 (Ensembl)
WNT10AGeneProductENSG00000135925 (Ensembl)
WNT10BGeneProductENSG00000169884 (Ensembl)
WNT11GeneProductENSG00000085741 (Ensembl)
WNT16GeneProductENSG00000002745 (Ensembl)
WNT1GeneProductENSG00000125084 (Ensembl)
WNT2BGeneProductENSG00000134245 (Ensembl)
WNT2GeneProductENSG00000105989 (Ensembl)
WNT3AGeneProductENSG00000154342 (Ensembl)
WNT3GeneProductENSG00000108379 (Ensembl)
WNT4GeneProductENSG00000162552 (Ensembl)
WNT5AGeneProductENSG00000114251 (Ensembl)
WNT5BGeneProductENSG00000111186 (Ensembl)
WNT6GeneProductENSG00000115596 (Ensembl)
WNT7AGeneProductENSG00000154764 (Ensembl)
WNT7BGeneProductENSG00000188064 (Ensembl)
WNT8AGeneProductENSG00000061492 (Ensembl)
WNT8BGeneProductENSG00000075290 (Ensembl)
WNT9AGeneProductENSG00000143816 (Ensembl)
WNT9BGeneProductENSG00000158955 (Ensembl)

Annotated Interactions

No annotated interactions

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