Endochondral ossification (WP474)

Homo sapiens

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 [https://assays.cancer.gov/available_assays?wp_id=WP474 CPTAC Assay Portal]


Lars Eijssen , Alex Pico , Alla , Kristina Hanspers , Egon Willighagen , Susan Coort , Denise Slenter , and Eric Weitz


last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens



Cell Type Ontology

chondrocyte osteoclast obsolete osteochondroclast

Pathway Ontology

regulatory pathway


Label Type Compact URI Comment
Oxygen Metabolite hmdb:HMDB0001377
Triiodothyronine Metabolite chebi:24864
Thyroid hormone Metabolite chebi:60311
Thyroid hormone Metabolite chebi:60311
cAMP Metabolite hmdb:HMDB0000058
AKP2 GeneProduct ncbigene:249
Osteopontin GeneProduct ncbigene:6696
FGFR3 GeneProduct ncbigene:2261
MMP13 GeneProduct ncbigene:4322
Aggrecan GeneProduct ncbigene:176
BMPR1A GeneProduct ncbigene:657
IHH GeneProduct ncbigene:3549
FGFR1 GeneProduct ncbigene:2260
IGF2 GeneProduct ncbigene:3481
BMP6 GeneProduct ncbigene:654
IGF1 GeneProduct ncbigene:3479
SLC38A2 GeneProduct ncbigene:54407
TGFBI GeneProduct ncbigene:7040
CAB39 GeneProduct ncbigene:51719
MEF2C GeneProduct ncbigene:4208
COL2A1 GeneProduct ncbigene:1280
ADAMTS5 GeneProduct ncbigene:11096
RUNX3 GeneProduct ncbigene:864
PTH GeneProduct ncbigene:5741
FGF18 GeneProduct ncbigene:8817
CALM1 GeneProduct ncbigene:801
Adseverin GeneProduct ncbigene:85477 PMID: 17097081
RUNX2 GeneProduct ncbigene:860
FGF2 GeneProduct ncbigene:2247
SOX6 GeneProduct ncbigene:55553
PTCH GeneProduct ncbigene:5727
NPP1 GeneProduct ncbigene:5167
PKA GeneProduct ncbigene:5566
KIF3A GeneProduct ncbigene:11127
PTCH1 GeneProduct ncbigene:5727
TNAP GeneProduct ncbigene:445341
RUNX2 GeneProduct ncbigene:860
C4ST1 GeneProduct ncbigene:50515
Cathepsin L2 GeneProduct ncbigene:1515 Taken as homologue to mouse Cathepsin L (Ctsl)
TGFB2 GeneProduct ncbigene:7042
AKT GeneProduct ncbigene:207
Growth hormone GeneProduct ncbigene:2688
GLI3 GeneProduct ncbigene:2737
HMGCS1 GeneProduct ncbigene:3157
VEGFA GeneProduct ncbigene:7422
MMP9 GeneProduct ncbigene:4318
SERPINH1 GeneProduct ncbigene:871
BMP7 GeneProduct ncbigene:655
CDKN1C GeneProduct ncbigene:1028
Sox9 GeneProduct ncbigene:6662
THRA GeneProduct ncbigene:7067
RUNX2 GeneProduct ncbigene:860
STAT1 GeneProduct ncbigene:6772
ADAMTS1 GeneProduct ncbigene:9510
THRA GeneProduct ncbigene:7067
GH receptor GeneProduct ncbigene:2690
PLAU GeneProduct ncbigene:5328
MGP GeneProduct ncbigene:4256
STAT5 GeneProduct ncbigene:6777
COL10A1 GeneProduct ncbigene:1300
ADAMTS4 GeneProduct ncbigene:9507
TGFB1 GeneProduct ncbigene:7040
IGF1R GeneProduct ncbigene:3480
TG737 GeneProduct ncbigene:8100
DDR2 GeneProduct ncbigene:4921
Bapx1 GeneProduct ncbigene:579
Carminerin GeneProduct ncbigene:1473 Taken as human homologue of mouse Cst10
PMID: 13679380
FrzB-1 GeneProduct ncbigene:2487
PLAT GeneProduct ncbigene:5327
HDAC4 GeneProduct ncbigene:9759
PTHrP GeneProduct ncbigene:5744
PTHR1 GeneProduct ncbigene:5745
SOX5 GeneProduct ncbigene:6660
TIMP3 GeneProduct ncbigene:7078


  1. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Int J Biochem Cell Biol. 2008;40(1):46–62. PubMed Europe PMC Scholia
  2. A microarray approach for comparative expression profiling of the discrete maturation zones of mouse growth plate cartilage. Belluoccio D, Bernardo BC, Rowley L, Bateman JF. Biochim Biophys Acta. 2008 May;1779(5):330–40. PubMed Europe PMC Scholia
  3. The effect of dexamethasone and triiodothyronine on terminal differentiation of primary bovine chondrocytes and chondrogenically differentiated mesenchymal stem cells. Randau TM, Schildberg FA, Alini M, Wimmer MD, Haddouti EM, Gravius S, et al. PLoS One. 2013 Aug 16;8(8):e72973. PubMed Europe PMC Scholia