WISP3 - IGF1 interaction regulates chondrocyte hypertrophy

Abstract

Summary WISP3 (Wnt induced secreted protein 3) is a multi-domain protein of mesenchymal origin. Mutations in several domains of WISP3 cause PPRD (progressive pseudo rheumatoid dysplasia), which is associated with cartilage loss and restricted skeletal development. Despite several studies focusing on the functional characterization of WISP3, the molecular details underlying the course of PPRD remain unresolved. We are interested in analyzing the function of WISP3 in the context of cartilage integrity. The current study demonstrates that WISP3 binds to insulin-like growth factor 1 (IGF1) and inhibits IGF1 secretion. Additionally, WISP3 curbs IGF1-mediated collagen X expression, accumulation of reactive oxygen species (ROS) and alkaline phosphatase activity, all of which are associated with the induction of chondrocyte hypertrophy. Interestingly, both IGF1 and ROS in turn trigger an increase in WISP3 expression. Together, our results are indicative of an operational WISP3-IGF1 regulatory loop whereby WISP3 preserves cartilage integrity by restricting IGF1-mediated hypertrophic changes in chondrocytes, at least partly, upon interaction with IGF1.

CCN6 regulates mitochondrial function

“…In the light of previous findings demonstrating CCN6 as regulating total cellular ROS (Miller and Sen, 2007;Repudi et al, 2013), we examined if CCN6 influences mitochondrial ROS accumulation in association with mitochondrial ATP synthesis and Ca 2+ at the steady state. Our investigation was furthermore prompted by several reports documenting the interrelation of mitochondrial ROS, ATP and Ca 2+ (Brookes et al, 2004;Lehninger, 1970).…”

“…S4C). The appearance of such features could correlate with the expression of chondrocyte hypertrophy markers, such as collagen X, which are associated with CCN6 depletion (Repudi et al, 2013). It will be interesting to investigate how CCN6 expression and mitochondrial morphology correlate with other cellular transformations that accompany hypertrophic differentiation (Buckwalter et al, 1986;Goldring et al, 2006).…”

“…CCN6, or Wnt-induced signaling protein 3 (WISP3), is a 354-aminoacid protein that can function both intracellularly and extracellularly (Brigstock et al, 2003;Davis et al, 2006;Miller and Sen, 2007;Pal et al, 2012;Perbal, 2013;Repudi et al, 2013). WISP3 gets its name from its sequence homology with other WISP (CCN)-family members that are induced by Wnt1 (Pennica et al, 1998;Sen et al, 2004).…”

“…On account of the established link of CCN6 with PPRD, a comprehensive characterization of its function at the molecular level is important. CCN6 has been shown to modulate both IGF1-induced as well as basal expression of cartilage hypertrophy markers, such as reactive oxygen species (ROS) (Miller and Sen, 2007;Repudi et al, 2013). Other functions of CCN6 that might be useful in the context of cartilage growth and/or maintenance remain to be deciphered.…”

“…Given its influence on total cellular ROS accumulation (Miller and Sen, 2007;Repudi et al, 2013), we wanted to investigate if CCN6 controls mitochondrial ROS by regulating the mitochondrial electron transport chain (ETC). Perhaps the loss of a functional cartilage and the aberrant matrix mineralization associated with CCN6 mutations in individuals with PPRD (Dalal et al, 2012;Ekbote et al, 2013;Garcia Segarra et al, 2012;Hurvitz et al, 1999;Liu et al, 2015;Luo et al, 2015;Yang et al, 2013) are due to an imbalance in cell differentiation and/or hypertrophy, arising partly from altered mitochondrial function.…”