Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene ( Npr3 )

Abstract

In 1979, a BALB͞cJ mouse was identified with an exceptionally long body. This phenotype was found to be caused by a recessive mutation, designated longjohn (lgj), that mapped to the proximal region of chromosome 15. Several years later, a mouse with a similarly elongated body was identified in an outbred stock after chemical mutagenesis with ethylnitrosourea. This phenotype also was caused by a recessive mutation, designated strigosus (stri). The two mutations were found to be allelic. A third allele was identified in a DBA͞2J mouse and was designated longjohn-2J (lgj 2J ). Analysis of skeletal preparations of stri͞stri mice indicated that the endochondral ossification process was slightly delayed, resulting in an extended proliferation zone. A recent study reported that mice overexpressing brain natriuretic peptide, one of the members of the natriuretic peptide family, exhibit a skeletal-overgrowth syndrome with endochondral ossification defects. The Npr3 gene coding for type C receptor for natriuretic peptides (NPR-C), which is mainly involved in the clearance of the natriuretic peptides, mapped in the vicinity of our mouse mutations and thus was a candidate gene. The present study reports that all three mutations involve the Npr3 gene and provides evidence in vivo that there is a natriuretic-related bone pathway, underscoring the importance of natriuretic peptide clearance by natriuretic peptide type C receptor.

Musclin is an activity-stimulated myokine that enhances physical endurance

“…Thus, it has been suggested that musclin function may be due to modulation of the action of NPs by competition with them for clearance via NPR C binding (8,9). Indeed, musclin overexpression in osteoblast-lineage cells has been shown to result in elongated bones and marked kyphosis (9), which is similar to the phenotype of mice transgenically overexpressing BNP (10) or CNP (11) or lacking NPR C (12,13). However, the physiological role of musclin production in skeletal muscles has remained elusive.…”

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

“…NPR3-knockout mice show abnormalities of the skeleton, in particular a defect of endochondral ossification. 43 WISP-1 belongs to the CCN family and has been shown to support BMP-2-induced osteoblastic differentiation. 44 In vivo, in a model of fracture, WISP-1 is expressed in mesenchymal cells that surround the site of the injury.…”

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

“…Three different loss-of-function mutations in the murine NPR-C gene result in skeletal overgrowth [193]. In these mutant mice, a decrease in endogenous CNP clearance by NPR-C appears to activate the CNP/GC-B pathway.…”