Table 1: Comparative genetics of endochondral ossification/osteoarthritis.

Gene or pathway	Role in Endochondral Ossification	Implication in OA	Selected references
Col10a1 (type X collagen)	Secreted by hypertrophic chondrocytes	Increase in type X collagen as chondrocytes lose their ‘articular cartilage identity’ and become hypertrophic and calcified	[40,41]
PTHrP	Secreted by cells in the perichondrium, acts to keep chondrocytes proliferating and to prevent differentiation	Increased production of PTHrP by synovial fibroblasts in human OA, although decreased levels of PTH1R (its receptor) in rabbit OA	[42 and reviewed in 43]
Runx2	Stimulates chondrocyte hypertrophy and osteoblast differentiation	Upregulated in cartilage during early stages of OA	[44-46]
Hif2a	Transcriptionally activates Runx2	Highly expressed in OA cartilage, overexpression leads to cartilage destruction	[17,47]
Mmp-13 (Collagenase 3)	Required in the growth plate to prevent premature hypertrophy	Increased expression in OA cartilage leading to catabolism of Type II cartilage	[48,49]
Sox9	Required for expression of a number of cartilage specific genes, including type II collagen	Levels are decreased in OA. Reintroduction of Sox9 leads to increased synthesis of cartilage matrix	[50,51]
Gdf5	Required for correct cartilage development and joint placement	SNPs in Gdf5 associated with disease onset in multiple cohorts	[52,53]
Frzb	Expressed during chondrocyte condensation and promotes chondrocyte maturation	SNPs in Frzb associated with OA in some cohorts but not in others	[54-57]
Hedgehog signalling	Indian Hedgehog is produced by prehypertrophic chondrocytes and regulates both hypertrophic differentiation and chondrocyte proliferation	Increased hedgehog (Hh) signalling levels lead to increased OA severity, modulation of Hh signalling can reduce OA severity	[18,58]
Bmp and TGFbeta	Antagonistic interactions in the growth plate in the control of chondrocyte proliferation and hypertrophy	Implicated in osteophyte formation	[59,60]
Sulf2	Endochondral ossification, mutations lead to vertebral fusions changes and growth plate dynamics	Increased expression in osteoarthritic cartilage	[12,61]
COL11A1	Important for normal differentiation and spatial organization of growth plate chondrocytes	Reduced expression in OA cartilage. Heterozygotes show higher levels of MMP13 and reduced tensile stiffness in articular cartilage. COL11A1 significantly associated with OA.	[14,62,63]
Chondroitin sulfatases	Designate early stages of stem/progenitor cell differentiation	CHST11 identified as an OA susceptibility gene via GWAS	[11,64]
Syndecan 4	Expressed during chondrocyte differentiation. Its deficiency inhibits chondrocyte proliferation	Mediates matrix degradation by controlling ADAMTS-5 through direct interaction with the protease and through regulating MAPK-dependent synthesis of MMP-3.	[64]
Erg	Transcription factor induced by Gdf5. Involved in maintaining chondrocyte differentiation and inhibiting maturation to hypertrophy	Conditional Erg mouse mutants at the joint are more susceptible to OA defects in aging and following surgically-induced OA	[66-68]