Nitric oxide, C-type natriuretic peptide and cGMP as regulators of endochondral ossification

Abstract

Coordinated proliferation and differentiation of growth plate chondrocytes is required for endochondral bone growth, but the mechanisms and pathways that control these processes are not completely understood. Recent data demonstrate important roles for nitric oxide (NO) and C-type natriuretic peptide (CNP) in the regulation of cartilage development. Both NO and CNP stimulate the synthesis of cGMP and thus the activation of common downstream pathways. One of these downstream mediators, cGMP-dependent kinase II (cGKII), has itself been shown to be essential for normal endochondral bone formation. This review summarizes our knowledge of the roles and mechanisms of NO, CNP and cGKII signaling in cartilage and endochondral bone development.

Figure 1. Scheme of endochondral bone formation during development

Initially the mesenchyme in the region of the future bone anlage differentiates into chondrocytes, forming a cartilage model of the future bone (A). Cells in the center of the cartilage model undergo further differentiation into hypertrophic cells inducing vascular invasion of the diaphysis and formation of a marrow cavity. As a result of osteoclast and osteoblast activity, the cartilage is resorbed and the first osteoid is deposited (B). Areas of secondary ossification develop in the epiphysis, while in the growth plate (gp), located between the epiphysis and diaphysis, columns of chondrocytes continue to proliferate, hypertrophy, secrete and mineralize the extracellular matrix (C). Over time this matrix is partially resorbed and replaced with new bone resulting in bone elongation.

Figure 2. Scheme of cGMP pathways active in growth plate cartilage

Nitric oxide (NO) generation by nitric oxide synthases (NOS) present in chondrocytes leads to activation of the soluble guanylate cyclase (sGC) and an increase in the intracellular levels of cGMP. Binding of the C-type natriuretic peptide (CNP) to the natriuretic peptide receptor B (NPR2) also increases cGMP levels in chondrocytes. The increase in cGMP concentration may lead to activation of phosphodiesterases (PDE), cGMP-regulated ion channels (ICH) and cGMP-dependent kinases (cGK). In particular, cGK II has been shown to play an important role in endochondral bone formation. Possible downstream pathways include the inhibition of nuclear translocation of the transcription factor Sox 9 (SOX9), and the repression of FGF signaling and ERK activation through Raf 1.