Journal Facts

Journal
BoneKEy Knowledge Environment
ISSN
1533-4368
Volume
Year
2001

Article Facts

Title
Natriuretic peptides, cGMP and growth plate development
DOI
10.1138/2001024
Author

Online Date
04/30/2001

Article Links

BoneKEy-Osteovision | Commentary

Natriuretic peptides, cGMP and growth plate development


DOI:10.1138/2001024

Growth plate development is a fascinating story of proliferation, differentiation and death. Growth plate chondrocytes go through well-ordered and controlled phases of cell proliferation, differentiation, and apoptosis (). Proliferative chondrocytes that synthesize high levels of collagen type II form a columnar layer, and then differentiate into post-mitotic hypertrophic cells that express predominantly collagen type X and produce angiogenic factors. Differentiation is followed by death of hypertrophic chondrocytes, blood vessel invasion and replacement of the cartilage matrix with a trabecular bone matrix.

A significant number of hormones and paracrine/autocrine factors have been shown to play a role in modulating this well organized and indeed tightly controlled process. In particular, it has become clear in recent years that activation of the cAMP signaling pathway is a critical event in growth plate development ().

Another interesting story that involves natriuretic peptides, cGMP and the chondrocytic growth plate is now unfolding. cGMP is involved in many physiological functions, such as smooth muscle relaxation, retinal phototransduction and intestinal secretion (). Intracellular cGMP levels are regulated by guanylate cyclases (GCs). GCs produce cGMP in response to natriuretic peptides and nitric oxide. Natriuretic peptides are a family of three structurally related peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) (). ANP and BNP act as cardiac hormones that are produced predominantly by the atrium and ventricle, respectively. CNP occurs in a wide variety of tissues, where it acts as a neuropeptide as well as a local regulator. Two subtypes of guanylyl cyclases (GC)-coupled natriuretic peptide receptors (GC-A or NPR-A and GC-B or NPR-B) have been cloned so far (). ANP and BNP are thought to be endogenous ligands for GC-A, whereas CNP is selective for GC-B. A third natriuretic peptide receptor that does not have guanylyl cyclase activity has been implicated in the metabolic clearance of ligands and thereafter named the clearance receptor (C-receptor or NPR-C) ().

The first in vitro evidence that NPs could be modulators of chondrocyte activity was reported in 1994 (); four years later a transgenic experiment performed to study BNP role in heart function revealed that NPs may be important regulators of skeletal growth in vivo (). Consistent with this notion, mice deficient in type II cGMP-dependent protein kinase develop impaired endochondral ossification (). Furthermore, animals lacking the natriuretic peptide clearance receptor NPR-C display a skeletal overgrowth phenotype (). But then the questions: which NP is the relevant peptide in growth plate development and how? Knockout experiments as well as transgenic overexpression have convincingly ruled out ANP and GC-A as putative modulators of chondrocyte activity (). A recent study published by Chusho et al. in Proc Natl Acad Sci () adds a formerly lacking piece to the puzzle, by providing evidence that CNP is likely to be a physiological regulator of chondrocyte proliferation and differentiation. Chusho et al. report that mice with targeted disruption of CNP (Nppc-/-) are dwarfed. The growth plate from these mutant animals is narrow, and it displays decreased BrdU incorporation, reduced heights of both the proliferative and hypertrophic zones, and a reduced ratio of the height of the hypertrophic zone to the height of the proliferative zone. Taken together, the lack of CNP seems to decrease both the proliferation and differentiation rates of growth plate chondrocytes. Furthermore, the rescue of the growth plate abnormalities by local transgenic overexpression of CNP suggests that CNP may act in the growth plate as a local paracrine/autocrine factor. It is likely that the previously reported transgenic overexpression of BNP caused skeletal overgrowth and activation of endochondral bone formation through cross-reactivity with GC-B, which is the specific receptor for CNP and has been shown to be abundantly expressed in long bones (). Chusho's paper expands previous studies by the same group and others showing that CNP treatment increases the bone longitudinal length by activating both chondrocyte proliferation and differentiation (), and strongly support the working hypothesis that the CNP/GC-B/cGMP-dependent protein kinase II signaling cascade is likely to play a critical role in endochondral bone formation.

The story of NPs and growth plate development is, however, still far from being completed unfolded. Mice that lack protein kinase II show a growth plate disorganization that is not present in the Nppc-/- animals (). Furthermore, cGMP has been previously reported to reproduce some but not all the effects of CNP in chondrocytes, suggesting that other signal transduction mechanisms may also be involved (). To add complexity to the picture, there is evidence that cGMP effects may also be mediated in some cell types by cross-activation of cAMP-dependent protein kinase A (), a crucial modulator of chondrocyte activity. Lastly, the phenotype of the Nppc-/- is reminiscent of achondroplasia, which is the most common form of dwarfism in humans and is caused by constitutively active FGFR3 receptors (). Are CNP and FGFs somehow associated in coordinating growth plate development? It is clear that a few pieces of the puzzle are still missing.

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