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Pharmacological and Physiological Sciences St. Louis University School of Medicine St. Louis, Missouri 63104
Address all correspondence and requests for reprints to: Willis K. Samson, Ph.D., Pharmacological and Physiological Sciences, St. Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, Missouri 63104. E-mail: samsonwk{at}slu.edu
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Introduction |
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The natriuretic peptide family is comprised of at least three major isoforms. The first peptide identified came from cardiac extracts and thus was named atrial (for its presumed origin) natriuretic (for its first identified action) peptide, ANP. It did not take long for additional tissue sites of production to be identified including adrenal gland, brain, and pituitary. Similarly, multiple tissue sites of action in addition to the vasculature and kidney were reported, and soon investigators in the field took on the challenge of making sense of all these diverse biologic, or at least pharmacologic, actions (2). Some unifying aspects of the multiple tissue targets and phenotypic responses to ANP have been uncovered and the pathophysiologic relevance of those relationships exploited, in particular the role played by the NPs in volume regulation and cardiovascular response to volume overload (2).
Soon after the discovery of ANP, a second peptide was sequenced. It was given the unfortunate name BNP, not following the alphabet, but instead identifying the tissue source from which it was isolated, porcine brain, hence brain natriuretic peptide (BNP). This was clearly, as many have reported, a misnomer because the brain is a very poor source of BNP. The peptide also is produced in the heart, and then primarily during pathologic conditions. When the third member of the family was identified, the field had come to its senses and the alphabet was followed. In a strange twist of fate, however, this peptide, designated C-type natriuretic peptide (CNP), did not exert remarkable natriuretic effects in vivo and was in fact the major form of the NPs produced in nervous tissue. So CNP would probably be better to have been designated BNP, but it is too late for such a rectification.
The difficult work was not the clarification of nomenclature but the identification of physiologic relevance, and as part of that search, multiple NP receptor isoforms were identified. Remarkable discoveries were made along the way. Two of the isoforms turned out to be not merely linked to guanylyl cyclases, but to be indeed guanylyl cyclase molecules themselves (3). Originally designated natriuretic peptide-A and -B receptors, the convention soon became that they were called GC-A and GC-B receptors, reflecting the result of their activation. A third receptor, the NPR-C receptor, was initially not thought to express any biologic activity (i.e. to be devoid of a unique signaling component) and became the prototype of the clearance receptor (4). However, it is now known that the NPR-C receptor does link NP binding to distinct signaling pathways with clear biologic consequence (5).
Because the GC-A and GC-B receptors share extensive sequence homology in the extracellular binding domain, and even more homology in the kinase and cyclase domains, it is not surprising that the two peptides share many biologic actions. In fact ANP is the preferred ligand for the GC-A receptor, with BNP a close second, and CNP a poor third. On the other hand, the preferred ligand for the GC-B receptor is CNP, with relatively less affinity expressed for ANP and BNP. The distributions of receptor subtypes also differ, with GC-A most abundant in the vasculature, and GC-B prevailing in brain. Both receptors are expressed in adrenal gland and kidney. While in brain it is clear that the major biologically responsive receptor is the GC-B isoform, in the periphery things aren’t so straightforward. It has remained a major challenge to identify tissue-specific effects of the NPs that rely upon the presence of the GC-A vs. the GC-B receptor subtypes.
A major breakthrough in that effort came with the description by the Garbers lab of mice lacking the GC-A receptor (6). These animals were hypertensive, thus indicating the physiologic relevance of the actions of the NPs in the vasculature and possibly the kidney. Similar conclusions were drawn from the phenotype observed in the ANP knockout mouse (7). These studies, however, could not separate out the role(s) played by the GC-B or the NPR-C receptors, and particularly in the case of the ANP-knockout mice, the remaining BNP could be a substitute for its missing homolog. Attempts at overexpression of ANP met with some success, but it was the BNP transgene that created intense interest. As possibly expected, animals overexpressing BNP were hypotensive. Surprisingly, however, these animals also displayed a skeletal phenotype characterized by marked overgrowth caused by endochondrial ossification (8). It had already been recognized that the GC-B receptor was present in clonal murine calvarial MC3T3-E1 cells and that CNP, but at the doses tested not ANP, increased cGMP production in those cells. CNP, which is produced in MC3T3-EI cells, also increased type-I collagen, cellular alkaline phosphatase, and osteocalcin messenger RNA (mRNA) levels, suggesting a role for endogenous, bone-derived CNP in osteoblastic differentiation (9). Similar effects of CNP had been observed in rat chondrocytes (10) and osteoblast-like cells from neonatal rat calvaria (11).
Chusho and colleagues (1) cross-mated mice overexpressing BNP (BNP-Tg) with GC-A deficient (GC-A-/-) mice and observed that the BNP-Tg/GC-A-/- were hypertensive as were the GC-A-/- mice. This indicated that overexpression of BNP, which by itself results in hypotension, could not rescue the hypertensive state of GC-A absence. Clearly the vascular effect of BNP is expressed via the GC-A receptor. However, the skeletal overgrowth observed in the BNP transgenic animals was still present in the mice lacking the GC-A receptor. Thus, it is apparent that circulating BNP can exert tissue specific actions via more than one NP receptor subtype, and that it is in all likelihood the GC-B receptor in bone that transduces the effects of BNP overexpression.
Does this mean that endogenous BNP is a physiologically relevant regulator of bone formation? No, it certainly does not. In fact, the BNP effect in all likelihood reflects a role for endogenous CNP. Both CNP and BNP (albeit at high concentrations, like those attained in the BNP-Tg) can activate the GC-B receptor, which Chusho et al. (1) now have demonstrated to be present in the proliferative and prehypertrophic zones of the growth plate. Furthermore, they reveal that, in a yet-to-be published study, they have overexpressed CNP under the control of the chondrocyte-specific type II collagen promoter and observed similar endochondrial ossification and skeletal overgrowth. Therefore, it appears more and more likely that endogenous CNP can be a major determinant of bone formation under physiologic or pathophysiologic states.
Many questions remain, however, and those questions may be the most difficult to answer. Not only is the GC-B receptor expressed in bone, but also abundant NPR-C receptor is present as well. Indeed, 1,25-Dihydroxyvitamin D3 increases NPR-C mRNA stability and, importantly, attenuated intracellular cGMP accumulation stimulated by CNP, without changing GC-B receptor mRNA levels (12). Thus, changes in clearance receptor number or affinity for the NPs may be a physiologically relevant determinant of the actions of endogenous peptides on bone formation by removing available CNP, of local origin, or circulating ANP and BNP of cardiac origin from the bone interstitium. Evidence for such a role for the clearance receptor comes from recent work from the Smithies lab (13) in which skeletal deformity was observed in mice lacking the NPR-C. It was hypothesized by these authors that in the absence of the clearance receptor, more endogenous NP is available for binding to the GC-A in the vasculature (hence the observed hypotensive state) and the GC-B in bone (and thus the skeletal deformity). While it is becoming clear that the GC-B in bone is the end biologic effector of the actions of the NPs, particularly endogenous CNP, a complete understanding of the regulation of these actions of the NPs under physiologic and pathophysiologic conditions will require intense scrutiny of the regulation not only the production of local CNP but also the delicate balance of the activity of the clearance (NPR-C) and the biologic (GC-B) receptors in bone. Already some information is available on the regulation of GC-B expression in an osteogenic cell line (14). Certainly those descriptive studies will facilitate the further understanding of bone biology and the search for a potential therapeutic use for the NPs or their analogs. It would be nice to know what happens when the GC-B receptor is deleted as well, and without a doubt that information will be soon available, given the track record of the excellent laboratories contributing to this literature.
Received July 24, 2000.
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