Inducible nitric oxide synthase–nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth

Abstract

SummaryCoordinated proliferation and differentiation of growth plate chondrocytes controls endochondral bone growth and final height in humans, and disruption of this process results in diseases of the growing and adult skeleton, such as chondrodysplasias or osteoarthritis. We had shown recently that chondrocyte-specific deletion of the gene Rac1 in mice leads to severe dwarfism due to reduced chondrocyte proliferation, but the molecular pathways involved remained unclear. Here, we demonstrate that Rac1-deficient chondrocytes have severely reduced levels of inducible nitric oxide synthase (iNOS) protein and nitric oxide (NO) production. NO donors reversed the proliferative effects induced by Rac1 deficiency, whereas inhibition of NO production mimicked the effects of Rac1 loss of function. Examination of the growth plate of iNOS-deficient mice revealed reduced chondrocyte proliferation and expression of cyclin D1, resembling the phenotype of Rac1-deficient growth plates. Finally, we demonstrate that Rac1-NO signaling inhibits the expression of ATF3, a known suppressor of cyclin D1 expression in chondrocytes. In conclusion, our studies identify the iNOS-NO pathway as a novel mediator of mitogenic Rac1 signaling and indicate that it could be a target for growth disorder therapies.

Identification and Validation of Quantitative Trait Loci (QTL) for Canine Hip Dysplasia (CHD) in German Shepherd Dogs

“…Inhibition of Rac1 expression in micromass culture resulted in reduced mRNA levels of the chondrogenic markers collagen II and aggrecan, and decreased accumulation of glycosaminoglycans indicating that Rac1 promotes chondrogenesis [28]. Rac1-deficient chondrocytes had severely reduced levels of inducible nitric oxide synthase protein (iNOS) and nitric oxide production [29]. Mice deficient for iNOS had reduced chondrocyte proliferation and resembled the phenotype of Rac1-deficient growth plates.…”

Knee loading reduces MMP13 activity in the mouse cartilage

“…Rac1 is necessary for development and maintenance of cartilage [26], and its chondrocyte-specific deletion results in severe dwarfism in mice [27]. In response to fibronectin fragments, it is reported that Rac1 is required for the production of MMP13 in chondrocytes [28].…”

Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1

“…Although low and variable levels of nitric oxide are essential during endochondral ossification, catabolic and homeostatic activity in human cartilage (Amin et al, 1999;Wang et al, 2011), high levels of NO have detrimental effects in cartilage . Granted that HMGB1 can bind to a multitude of known receptors in chondrocytes, the functional receptor for HMGB1 in human OA-affected cartilage remains elusive.…”