Table III.

Targeting CCNs in animal models of disease

Disease/ pathology	CCN proteins	Animal model	Phenotypes/intervention	Refs.
Fibrosis	CCN1	• Wound healing in α6β1-binding defective Ccn1 knockin mice	• Enhanced fibrosis in cutaneous wounds; topical application of CCN1 reverses effect	8
	CCN2	• Transgenic mice overexpressing CCN2 in hepatocytes	• Exacerbated liver fibrosis induced by CCl4 or bile duct ligation	182
		• Mouse liver fibrosis (CCl4)	• CCN2 siRNAs reduce fibrosis	74
		• N-nitrosodimethylamine-induced liver fibrosis	• CCN2 siRNAs reduce fibrosis	75
		• Streptozotocin (STZ)-induced diabetes in podocyte-specific Ccn2 transgenic mice	• Exacerbated renal hypertrophy, proteinuria, and mesangial matrix expansion	134
		• Tubulointerstitial fibrosis induced by unilateral ureteral obstruction	• Reduction of ECM induction by CCN2 AS-ODN	76
		• Subtotal nephrotectomy in TGF-β1 transgenic mice	• CCN2 AS-ODN blocked interstitial fibrosis in remnant kidney	78
		• Cardiomyocyte-specific Ccn2 transgenic rodents; angiotensin II-induced pressure overload heart failure	• No cardiac fibrosis; promotes cardiac hypertrophy and protects against pressure-overload heart failure	149
		• Deletion of Ccn2 in fibroblasts and smooth muscle cells	• Resistant to bleomycin-induced skin fibrosis	72
		• Fibroblast-specific Ccn2 transgenic mice	• Fibrosis in skin, lung, kidney, and vasculature	71
	CCN4	• Bleomycin-induced pulmonary fibrosis	• Neutralizing antibodies attenuates lung fibrosis	79
	CCN5	• Transverse aortic constriction in Ccn5 transgenic mice	• Inhibition of pressure overload-induced cardiac hypertrophy and fibrosis	82
Cancer	CCN1	• Glioma xenografts	• siRNA inhibited pre-established glioma growth	101
		• Pancreatic cancer cells	• shRNA reverses characteristics of EMT and reduced tumorigenicity	95 94
	CCN2	• Pancreatic cancer xenografts
		• Orthotopic and xenografted pancreatic cancer	• Decreased tumor growth with shCCN2 or siCCN2	104
			• FG-3019 attenuates tumor growth and metastasis	105
Cardio-vascular disease	CCN1	• Rat carotid artery balloon injury	• CCN1 siRNAs suppress neointimal hyperplasia	145
	CCN1	• Mouse autoimmune myocarditis	• Adenoviral expression of CCN1 attenuates myocarditis	47
	CCN2	• Rat carotid artery angioplasty with viral perfusion	• Recombinant CCN2 application increased neointimal thickening	143
Nephropathy/Retinopathy	CCN1	• Mouse oxygen-induced retinopathy (OIR)	• Intravetreal injection of anti-CCN1 antibody reduced retinal neovascularization	138
	CCN2	• Streptozotocin (STZ)-induced diabetic mice	• Subcutaneous CCN2 AS-ODN decreased proteinuria and albuminuria	133
			• Reduced basal lamina thickening of retinal capillaries in Ccn2+/− background	140
Wound healing	CCN1	• Bone fracture (transverse osteotomy)	• Intraperitoneal injection of anti-CCN1 antibody impaired fracture healing	154
	CCN2	• Rabbit punch wound at ears	• Intradermal CCN2 AS-ODN injection reduced hyperptrophic scarring	77

AS-ODN, antisense oligonucleotide