Clinical significance and implications of genetic and genomic studies in patients with osteoarthritis

Figures & data

Table 1 Cartilage ECM protein gene mutations: association with musculoskeletal diseases

Protein	Genes	Medical conditions	Chondrodysplasia	OA	Reference
Collagen II	COL2AI	Stickler syndrome	Yes	Possibly	38
		Achondrogenesis II	Yes	No	38
		Hypochondrogenesis	Yes	No	38
		Spondyloepiphyseal dysplasia	Yes	Possibly	38
		Precocious OA	Possibly	Yes	28,29
Collagen IX	COL9AI	Multiple epiphyseal dysplasia	Yes	Possibly	33,34
	COL9A2	Lumbar disk disease	No	No	38
	COL9A3	Precocious OA	No	Yes	38
Collagen XI	COLIIAI	Stickler syndrome	Yes	Possibly	38
	COLIIA2	Spondylomegaepiphyseal dysplasia	Yes	Possibly	38
		Precocious OA	No	Yes	38
Aggrecan	ACAN	Chondrodysplasias	Yes	Possibly	38
		Osteochondritis dessicans	No	Possibly	37
Asporin	ASPN	Premature OA	No	Yes	38
COMP	COMP	Pseudoachondroplasia	Yes	Possibly	38
		Multiple epiphyseal dysplasia	Yes	Possibly	38
		Early-onset OA	No	Yes	43
		Hip and knee OA	No	Yes	44
Matrilin-3	MATN3	Multiple epiphyseal dysplasia	Yes	Possibly	38
		Spondyloepimetaphyseal dysplasia	Yes	Possibly	38
		Precocious OA	No	Yes	46–48
Lubricin	PRG4	Camptodactyly-arthropathy-coxa vara-pericarditis syndrome	No	Possibly	50,51

Abbreviations: OA, osteoarthritis; COMP, cartilage oligomeric matrix protein; ECM, extracellular matrix.

Figure 1 Non-ECM genes identified as OA candidate genes.

Notes: Four non-ECM protein genes (growth differentiation factor-5 [GDF5], secreted Frizzle-related protein-3 [FRZB], diodinase-2 [DIO2], and calmodulin-1 [CALM1]) have been shown by GWAS to be potential candidate OA susceptibility genes.^58–62 GDF5 is a member of the TGF-β protein family. SNPs in GDF5 may be associated with altered chondrocyte signal transduction and Wnt3a responses. FRZB is a Wnt/β-catenin antagonist. SNPs in FRZB were shown to increase the frequency of chondrocyte apoptosis. DIO2 is an initiator of thyroid hormone signaling. SNPs in DIO2 have been associated with acceleration of articular chondrocyte hypertrophy and the emergence of a proinflammatory phenotype. CALM1 is a calcium-modulating protein that is overexpressed in OA cartilage. SNPs in CALM1 were shown to be associated with altered chondrocyte proliferation and signal transduction. Adapted from: Mototani H, Mabuchi A, Saito S, et al, A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese, Hum Mol Genet, 2005;14(8):1009–1017, by permission of Oxford University Press;⁵⁹ and Cornelis FM, Luyten FP, Lories RJ. Functional effects of susceptibility genes in osteoarthritis. Discov Med 12(63):129-139, August 2011. Copyright © Discovery Medicine.⁶²
Abbreviations: GWAS, genome-wide association studies; OA, osteoarthritis; TGF, transforming growth factor; SNP, single nucleotide polymorphism; ECM, extracellular matrix.

Loughlin J. Polymorphism in signal transduction is a major route through which osteoarthritis susceptibility is acting. Curr Opin Rheumatol. 2005;17(5):629–633.

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Cornelis FM, Luyten FP, Lories RJ. Functional effects of susceptibility genes in osteoarthritis. Discov Med. 2011;12(63):129–139.

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Mototani H, Mabuchi A, Saito S, et al. A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese. Hum Mol Genet. 2005;14(8):1009–1017.

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