Abstract
Recent studies revealed C-type natriuretic peptide (CNP) and its receptor, guanylyl cyclase-B (GC-B) are potent stimulators of endochondral bone growth. As they exist ubiquitously in body, we investigated the physiological role of the local CNP/GC-B in the growth plate on bone growth using cartilage-specific knockout mice. Bones were severely shorter in cartilage-specific CNP or GC-B knockout mice and the extent was almost the same as that in respective systemic knockout mice. Cartilage-specific GC-B knockout mice were shorter than cartilage-specific CNP knockout mice. Hypertrophic chondrocyte layer of the growth plate was drastically reduced and proliferative chondrocyte layer, along with the proliferation of chondrocytes there, was moderately reduced in either cartilage-specific knockout mice. The survival rate of cartilage-specific CNP knockout mice was comparable to that of systemic CNP knockout mice. The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth and might further affect mortality via unknown mechanisms.
Highlights
The full-length gel is presented in Supplementary Figure S1. (c) Quantitative real-time RT-PCR analysis for C-type natriuretic peptide (CNP) expression in Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. (d) Immunohistochemical analysis of CNP in growth plates of Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. (e) Gross appearance of Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. (f) Growth curves of naso-tail lengths of Nppcflox/flox (■) and
Growth of vertebrae and long bones[16,17]. Given that both CNP and guanylyl cyclase (GC)-B are expressed in the growth plate cartilage of vertebrae and long bones[16], it is possible that the local CNP/GC-B system in the growth plate contributes in some way to physiological endochondral bone growth
As for skeletal tissue, we had elucidated that the CNP/GC-B system directly stimulates endochondral bone growth in the growth plate; CNP stimulates tibial explants from fetal mice in organ culture[31], and mice with targeted overexpression of CNP in the growth plate exhibit prominent skeletal overgrowth phenotype[32]
Summary
The full-length gel is presented in Supplementary Figure S1. (c) Quantitative real-time RT-PCR analysis for CNP expression in Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. (d) Immunohistochemical analysis of CNP in growth plates of Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. (e) Gross appearance of Nppcflox/flox (upper) and Col2a1-Cre; Nppcflox/flox (lower) mice. (f) Growth curves of naso-tail lengths of Nppcflox/flox (■) and. (c) Quantitative real-time RT-PCR analysis for CNP expression in Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. (d) Immunohistochemical analysis of CNP in growth plates of Nppcflox/flox and Col2a1-Cre; Nppcflox/flox mice. Growth of vertebrae and long bones[16,17] Given that both CNP and GC-B are expressed in the growth plate cartilage of vertebrae and long bones[16], it is possible that the local CNP/GC-B system in the growth plate contributes in some way to physiological endochondral bone growth. In the present study, we generated cartilage-specific CNP knockout mice using the Cre recombinase (Cre)-loxP system, which enables targeted depletion of an intended gene, and used these mice to investigate the physiological effects of CNP on endochondral bone growth in the growth plate. We knocked down GC-B in the growth plate in mice using the same Cre-loxP system, and further investigated the physiological roles of the CNP/GC-B system on endochondral bone growth there
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