Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis

K G F Gerritsen, N Bovenschen, T Q Nguyen, D Sprengers, M P Koeners, A N van Koppen, J A Joles, R Goldschmeding, R J Kok

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CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent pathway.

Original languageEnglish
Pages (from-to)295-303
Number of pages9
JournalJournal of Cell Communication and Signaling
Issue number4
Publication statusPublished - Dec 2016


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    Gerritsen, K. G. F., Bovenschen, N., Nguyen, T. Q., Sprengers, D., Koeners, M. P., van Koppen, A. N., Joles, J. A., Goldschmeding, R., & Kok, R. J. (2016). Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis. Journal of Cell Communication and Signaling, 10(4), 295-303. https://doi.org/10.1007/s12079-016-0354-6