Endochondral Ossification (Homo sapiens)

From WikiPathways

Revision as of 13:36, 18 December 2017 by DeSl (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
1-3CartilageRemoval of extracellular matrixand invasion by bone cellsProliferationGsBMPs?BoneChondrocyte deathHypertrophyChondrocyte proliferationDyingVascular invastionWNT signalingcanonical / non-canonicalMineralisationFull differentiationChondrocyte (pre)hypertrophyOsteoblasticdifferentiationintegrinsRemoval of cartilage matrixCathepsinsand CalpainsTHRATGFB2Thyroid hormoneMMP9PKADDR2PTCHBMPR1AFGFR1NPP1THRAPTHR1OsteopontinGH receptorTNAPTIMP3CDKN1CPTHAKP2BMP7SOX6Thyroid hormoneOxygenKIF3ACAB39CarminerinPLAUGrowth hormoneTG737C4ST1AggrecanGLI3SOX5IHHMMP13PTCH1RUNX3AdseverinIGF1RFrzB-1SERPINH1ADAMTS4cAMPSTAT5RUNX2AKTCathepsin L2RUNX2Sox9TGFBITriiodothyronineRUNX2TGFB1Bapx1PTHrPIGF1HMGCS1MEF2CFGF18COL10A1IGF2VEGFAFGFR3PLATBMP6STAT1COL2A1ADAMTS1FGF2CALM1MGPHDAC4SLC38A2ADAMTS5


Description

Endochondral ossification is the process by which the embryonic cartilaginous model of most bones contributes to longitudinal growth and is gradually replaced by bone. During endochondral ossification, chondrocytes proliferate, undergo hypertrophy and die; the cartilage extracellular matrix they construct is then invaded by blood vessels, osteoclasts, bone marrow cells and osteoblasts, the last of which deposit bone on remnants of cartilage matrix. The sequential changes in chondrocyte behaviour are tightly regulated by both systemic factors and locally secreted factors, which act on receptors to effect intracellular signalling and activation of chondrocyte-selective transcription factors. Systemic factors that regulate the behaviour of chondrocytes in growth cartilage include growth hormone and thyroid hormone, and the local secreted factors include Indian hedgehog, parathyroid hormone-related peptide, fibroblast growth factors and components of the cartilage extracellular matrix. Transcription factors that play critical roles in regulation of chondrocyte gene expression under the control of these extracellular factors include Runx2, Sox9 and MEF2C. The invasion of cartilage matrix by the ossification front is dependent on its resorption by members of the matrix metalloproteinase family, as well as the presence of blood vessels and bone-resorbing osteoclast (Mackie et al.)

Thyroid hormone and especially triiodothyronine induce morphological hypertrophy of chondrocytes, through binding to thyroid hormone receptors. Further, triiodothyronine increases the total collagen production in chondrocytes, as also terminal differentiation, but triiodothyronine also induces cell death through non-apoptotic modes of physiological death. Triiodothyronine acts by altering intracellular gene expression after receptor binding, and is crucial for growth, as receptor deficiencies lead to dwarfism and growth retardation. Thyroid hormone inhibits the PTHR1 gene, which encodes for a g-protein coupled receptor for parathyroid hormone (PTH) and PTH-like hormones. PTH receptors activate adenylyl cyclase and a phosphatidylinositol-calcium second messenger system. They control the levels of calcium in the blood and thus, ossification as they inhibit hypertrophy upon activation (Mackie, Randau, https://rarediseases.org/rare-diseases/jansen-type-metaphyseal-chondrodysplasia/ ). Oxygen acts upon RUNX2 and HDAC4 in the ossification process. HDAC4 is a class II histone deacetylase/acuc/apha family gene, and if tethered to a promoter, it represses transcription (https://www.ncbi.nlm.nih.gov/gene/9759). Via this mechanism, HDAC4 represses RUNX2 in the ossification process. RUNX2 is a member of the RUNX family of transcription factors, encoding a nuclear protein with an RUND DNA-binding domain. It induces osteoblastic differentiation and skeletal morphogenesis, as it acts upon the DNA and regulatory factors (https://www.ncbi.nlm.nih.gov/gene/860). Thus, RUNX2 acts directly upon chondrocytical hypertrophy. Cyclic adenosine monophosphate (cAMP) act upon protein kinase A (PKA), which phosphorylates proteins if activated. In this case it leads to the inhibition of Sox9 (https://www.nature.com/articles/nm.3314). Sox9 induces cell proliferation and inhibits hypertrophy and is regulating the transcription of the anti-müllerian hormone.

Quality Tags

Ontology Terms

 

Bibliography

  1. Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M; ''Endochondral ossification: how cartilage is converted into bone in the developing skeleton.''; Int J Biochem Cell Biol, 2008 PubMed
  2. Belluoccio D, Bernardo BC, Rowley L, Bateman JF; ''A microarray approach for comparative expression profiling of the discrete maturation zones of mouse growth plate cartilage.''; Biochim Biophys Acta, 2008 PubMed
  3. Randau TM, Schildberg FA, Alini M, Wimmer MD, Haddouti el-M, Gravius S, Ito K, Stoddart MJ; ''The effect of dexamethasone and triiodothyronine on terminal differentiation of primary bovine chondrocytes and chondrogenically differentiated mesenchymal stem cells.''; PLoS One, 2013 PubMed

History

View all...
CompareRevisionActionTimeUserComment
95499view13:36, 18 December 2017DeSlAdded additional literature reference, changed unconnected lines to graphical lines.
95498view13:33, 18 December 2017DeSlModified description
95497view13:32, 18 December 2017DeSlModified description
95220view17:50, 26 November 2017DeSlChanged unconnected lines to graphical lines (where applicable).
87977view13:18, 25 July 2016SusanOntology Term : 'regulatory pathway' added !
80208view20:59, 22 May 2015KhanspersReverted to version '05:03, 25 October 2013' by Khanspers
80164view21:19, 14 May 2015KhanspersAdded mir499a targeting of SOX6
72122view05:03, 25 October 2013EgonwAdded missing metabolite identifiers.
63180view20:42, 8 May 2013MaintBotUpdating gpml version
45241view18:23, 7 October 2011AlexanderPicoOntology Term : 'osteochondroclast' added !
45003view15:53, 6 October 2011LarsEijssenOntology Term : 'osteoclast' added !
45001view15:52, 6 October 2011LarsEijssenOntology Term : 'chondrocyte' added !
45000view15:47, 6 October 2011LarsEijssenModified description
44999view14:45, 6 October 2011LarsEijssenadapted types of groups where relevant
41222view23:45, 1 March 2011MaintBotRemoved redundant pathway information and comments
32442view17:18, 15 August 2009MaintBotFixed text labels
32115view13:50, 14 August 2009MaintBotFixed group labels
29737view22:33, 1 June 2009KhanspersModified categories
28899view15:55, 11 March 2009AllaPeriodical save, work in progress
21676view11:32, 14 November 2008MaintBot[[Pathway:Homo sapiens:Endochondral Ossification]] moved to [[Pathway:WP474]]: Moved to stable identifier
19039view11:03, 16 September 2008LarsEijssenTwo genes changed to CAPS
19033view09:44, 16 September 2008LarsEijssenadded some missing Entrez gene IDs, removed a duplicate gene SPP1, changed Gs into label
16584view19:30, 22 June 2008AlexanderPicoconnected example nodes to database
16120view12:00, 11 June 2008LarsEijssenfixed data node types
16118view11:28, 11 June 2008LarsEijssenNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADAMTS1GeneProduct9510 (Entrez Gene)
ADAMTS4GeneProduct9507 (Entrez Gene)
ADAMTS5GeneProduct11096 (Entrez Gene)
AKP2GeneProduct249 (Entrez Gene)
AKTGeneProduct207 (Entrez Gene)
AdseverinGeneProduct85477 (Entrez Gene) PMID: 17097081
AggrecanGeneProduct176 (Entrez Gene)
BMP6GeneProduct654 (Entrez Gene)
BMP7GeneProduct655 (Entrez Gene)
BMPR1AGeneProduct657 (Entrez Gene)
Bapx1GeneProduct579 (Entrez Gene)
C4ST1GeneProduct50515 (Entrez Gene)
CAB39GeneProduct51719 (Entrez Gene)
CALM1GeneProduct801 (Entrez Gene)
CDKN1CGeneProduct1028 (Entrez Gene)
COL10A1GeneProduct1300 (Entrez Gene)
COL2A1GeneProduct1280 (Entrez Gene)
CarminerinGeneProduct1473 (Entrez Gene)
  • Taken as human homologue of mouse Cst10
  • PMID: 13679380
Cathepsin L2GeneProduct1515 (Entrez Gene) Taken as homologue to mouse Cathepsin L (Ctsl)
DDR2GeneProduct4921 (Entrez Gene)
FGF18GeneProduct8817 (Entrez Gene)
FGF2GeneProduct2247 (Entrez Gene)
FGFR1GeneProduct2260 (Entrez Gene)
FGFR3GeneProduct2261 (Entrez Gene)
FrzB-1GeneProduct2487 (Entrez Gene)
GH receptorGeneProduct2690 (Entrez Gene)
GLI3GeneProduct2737 (Entrez Gene)
Growth hormoneGeneProduct2688 (Entrez Gene)
HDAC4GeneProduct9759 (Entrez Gene)
HMGCS1GeneProduct3157 (Entrez Gene)
IGF1GeneProduct3479 (Entrez Gene)
IGF1RGeneProduct3480 (Entrez Gene)
IGF2GeneProduct3481 (Entrez Gene)
IHHGeneProduct3549 (Entrez Gene)
KIF3AGeneProduct11127 (Entrez Gene)
MEF2CGeneProduct4208 (Entrez Gene)
MGPGeneProduct4256 (Entrez Gene)
MMP13GeneProduct4322 (Entrez Gene)
MMP9GeneProduct4318 (Entrez Gene)
NPP1GeneProduct5167 (Entrez Gene)
OsteopontinGeneProduct6696 (Entrez Gene)
OxygenMetaboliteHMDB01377 (HMDB)
PKAGeneProduct5566 (Entrez Gene)
PLATGeneProduct5327 (Entrez Gene)
PLAUGeneProduct5328 (Entrez Gene)
PTCH1GeneProduct5727 (Entrez Gene)
PTCHGeneProduct5727 (Entrez Gene)
PTHGeneProduct5741 (Entrez Gene)
PTHR1GeneProduct5745 (Entrez Gene)
PTHrPGeneProduct5744 (Entrez Gene)
RUNX2GeneProduct860 (Entrez Gene)
RUNX3GeneProduct864 (Entrez Gene)
SERPINH1GeneProduct871 (Entrez Gene)
SLC38A2GeneProduct54407 (Entrez Gene)
SOX5GeneProduct6660 (Entrez Gene)
SOX6GeneProduct55553 (Entrez Gene)
STAT1GeneProduct6772 (Entrez Gene)
STAT5GeneProduct6777 (Entrez Gene)
Sox9GeneProduct6662 (Entrez Gene)
TG737GeneProduct8100 (Entrez Gene)
TGFB1GeneProduct7040 (Entrez Gene)
TGFB2GeneProduct7042 (Entrez Gene)
TGFBIGeneProduct7040 (Entrez Gene)
THRAGeneProduct7067 (Entrez Gene)
TIMP3GeneProduct7078 (Entrez Gene)
TNAPGeneProduct445341 (Entrez Gene)
Thyroid hormoneMetaboliteCHEBI:60311 (ChEBI)
TriiodothyronineMetaboliteCHEBI:24864 (ChEBI)
VEGFAGeneProduct7422 (Entrez Gene)
cAMPMetaboliteHMDB00058 (HMDB)

Annotated Interactions

No annotated interactions

Personal tools