Endochondral Ossification with Skeletal Dysplasias (Homo sapiens)

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1-3MineralisationChondrocyte (pre)hypertrophyRemoval of cartilage matrixDyingProliferationRemoval of extracellular matrixand invasion by bone cellsOsteoblasticdifferentiationCathepsinsand CalpainsChondrocyte proliferationWNT signalingcanonical / non-canonicalBoneChondrocyte deathHypertrophyCartilage?BMPsintegrinsFull differentiationVascular invastionGsAKTADAMTS4CAB39AKP2PLAUTG737TNAPTHRASERPINH1Bapx1TGFB1MMP9FGFR1IGF2TIMP3DDR2CDKN1CThyroid hormoneRUNX2PTHrPPLATGLI3GH receptorThyroid hormoneHDAC4RUNX2STAT5IGF1RCathepsin L2BMPR1AC4ST1FGFR3MMP13COL10A1ADAMTS1FGF2AdseverinMGPSox9COL2A1HMGCS1CarminerincAMPTGFB2OsteopontinBMP7TGFBIPKARUNX3VEGFACALM1MEF2CIGF1TriiodothyroninePTHSOX5KIF3ANPP1ADAMTS5PTCHGrowth hormonePTCH1FrzB-1IHHSOX6SLC38A2OxygenRUNX2STAT1AggrecanPTHR1THRABMP6FGF18OMIM:100800AchondroplasiaOMIM:612247Crouzon Syndrome With Acanthosis NigricansOMIM:616482Achondroplasia, Severe, With Developmental Delay And Acanthosis NigricansOMIM:187601Thanatophoric Dysplasia, Type IIOMIM:187600Thanatophoric Dysplasia, Type IOMIM:602849Muenke SyndromeOMIM:146000HypochondroplasiaOMIM:610474Camptodactyly, Tall Stature, And Hearing Loss SyndromeOMIM:185900Chromosome 2q35 Duplication SyndromeOMIM:607778Acrocapitofemoral DysplasiaOMIM:112500Brachydactyly, Type A1OMIM:174700Polydactyly, Preaxial IvOMIM:146510Pallister-Hall SyndromeOMIM:175700Greig Cephalopolysyndactyly SyndromeOMIM:613848Osteogenesis Imperfecta, Type XOMIM:614732Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, And Genital AnomaliesOMIM:600002Eiken SyndromeOMIM:215045Chondrodysplasia, Blomstrand TypeOMIM:156400Metaphyseal Chondrodysplasia, Jansen TypeOMIM:119600Cleidocranial DysplasiaOMIM:245150Keutel SyndromeOMIM:156510Metaphyseal Dysplasia With Maxillary Hypoplasia With Or Without BrachydactylyOMIM:600430Chromosome 2q37 Deletion SyndromeOMIM:615465Hartsfield SyndromeOMIM:156500Metaphyseal Chondrodysplasia, Schmid TypeOMIM:101600Pfeiffer SyndromeOMIM:166250Osteoglophonic DysplasiaOMIM:271665Spondylometaepiphyseal Dysplasia, Short Limb-Hand TypeOMIM:613073Metaphyseal Anadysplasia 2OMIM:602111Spondyloepimetaphyseal Dysplasia, Missouri TypeOMIM:250400Metaphyseal Dysplasia, Spahr TypeOMIM:151210Platyspondylic Lethal Skeletal Dysplasia, Torrance TypeOMIM:156510Metaphyseal Dysplasia With Maxillary Hypoplasia With Or Without BrachydactylyOMIM:119600Cleidocranial DysplasiaOMIM:183900Spondyloepiphyseal Dysplasia CongenitaOMIM:609162Czech DysplasiaOMIM:184250Spondyloepimetaphyseal Dysplasia, Strudwick TypeOMIM:108300Stickler Syndrome, Type IOMIM:271700Spondyloperipheral DysplasiaOMIM:200610Achondrogenesis, Type IIOMIM:608805Avascular Necrosis Of Femoral Head, Primary, 1OMIM:156550Kniest Dysplasia


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.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Bibliography

  1. 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 Europe PMC Scholia
  2. 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 Europe PMC Scholia
  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 Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
109123view05:57, 18 February 2020RleeConnected unconnected line.
109092view03:02, 17 February 2020RleeModified description
109091view02:58, 17 February 2020RleeModified title
109090view02:57, 17 February 2020RleeNew 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)
OxygenMetaboliteHMDB0001377 (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)
cAMPMetaboliteHMDB0000058 (HMDB)

Annotated Interactions

No annotated interactions

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