Table 1.

Stages of endochondral ossification and relevant signalling peptides

Stage	Events	Signalling peptides
Resting	Home to stem-like cells Production of collagen types II, IX, and XI and the proteoglycan aggrecan	Ihh stimulates chondrocytes to produce PTHrP causing chondrocytes to divide Vitamin D receptors expressed BMP antagonists expressed
Proliferation	Cells undergo rapid mitosis Marked increase in production of type II collagen, aggrecan, perlecan	Stimulated by GH through the action of IGF Ihh maintains chondrocytes in proliferative phase via PTHrP Chondrocytes produce more Ihh BMP agonists expressed which promote mitosis FGF expressed to control proliferation Stimulated by Wnt signalling and β-catenin Down-regulated by Notch signals Down-regulated by oestrogen Stimulated by mTOR signalling
Hypertrophic	Chondrocytes cease dividing Cells increase in size Production of non-fibrillar collagen type X Remodelling of surrounding ECM, possibly from pressure exerted by expanding chondrocytes and hyaluronan-aggrecan complexes Mineralization of ECM Cells express MMPs Chondrocytes begin secreting VEGF	Triiodothyronine stimulates transition from proliferative to hypertrophic Vitamin D enhances hypertrophy Chondrocytes produce more Ihh which promotes their transition from proliferative to hypertrophic PTHrP signalling falls off BMP antagonists (Smad6/7) expressed which stop mitosis Inhibited by FGF Stimulated by β-catenin and canonical Wnt signals Inhibited by Notch, stimulated by mTOR Regulated by RUNX2
Calcification	Chondrocytes stop producing collagen type X Terminal differentiation of chondrocytes by unknown process: apoptosis, autophagy, transdifferentiation, hypoxia	Production of VEGF Mineralization of cartilage
Ossification	Invasion by blood vessels Invasion by osteoclasts, osteoblasts, hematopoietic components Production of lamellar bone	VEGF stimulates angiogenesis Osteoblasts, osteoclasts under systemic control by calcitonin, PTH, thyroid hormone, oestrogen

Note. BMP, bone morphogenic protein; ECM, extracellular matrix; FGF, fibroblast growth factor; GH, growth hormone; IGF, insulin-like growth factor ; Ihh, Indian hedgehog; MMPs, matrix metalloproteinases; mTOR, mammalian target of rapamycin; PTH, parathyroid hormone; PTHrP, parathyroid hormone receptor protein; RUNX2, runt-related transcription factor 2; VEGF, vascular endothelial growth factor; Wnt, wingless/Int-1