Circulatory C-type natriuretic peptide reduces mucopolysaccharidosis-associated craniofacial hypoplasia in vivo

Skeletal alterations in the head and neck region, such as midfacial hypoplasia, foramen magnum stenosis and spinal canal stenosis, are commonly observed in patients with mucopolysaccharidosis (MPS). However, enzyme replacement therapy (ERT), one of the major treatment approaches for MPS, shows limited efficacy for skeletal conditions. In this study, we analysed the craniofacial morphology of mice with MPS type VII, and investigated the underlying mechanisms promoting jaw deformities in these animals. Furthermore, we investigated the effects of C-type natriuretic peptide (CNP), a potent endochondral ossification promoter, on growth impairment of the craniofacial region in MPS VII mice when administered alone or in combination with ERT. MPS VII mice exhibited midfacial hypoplasia caused by impaired endochondral ossification, and histological analysis revealed increased number of swelling cells in the resting zone of the spheno-occipital synchondrosis (SOS), an important growth centre for craniomaxillofacial skeletogenesis. We crossed MPS VII mice with transgenic mice in which CNP was expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP. The maxillofacial morphological abnormalities associated with MPS VII were ameliorated by CNP expression, and further prevented by a combination of CNP and ERT. Histological analysis showed that ERT decreased the swelling cell number, and CNP treatment increased the width of the proliferative and hypertrophic zones of the SOS. Furthermore, the foramen magnum and spinal stenoses observed in MPS VII mice were significantly alleviated by CNP and ERT combination. These results demonstrate the therapeutic potential of CNP, which can be used to enhance ERT outcome for MPS VII-associated head and neck abnormalities

循環血中のC型ナトリウム利尿ペプチド(CNP)は軟骨異形成を示すCNPノックアウトマウスの骨伸長障害と早期の高い死亡率を改善する

京都大学0048新制・課程博士博士(医学)甲第15746号医博第3508号新制||医||984(附属図書館)28307京都大学大学院医学研究科内科系専攻(主査)教授 戸口田 淳也, 教授 稲垣 暢也, 教授 芹川 忠夫学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Voriconazole-induced periostitis in a patient with overlap syndromes.

A 52-year-old woman with overlap syndrome and interstitial pneumonia underwent immunosuppressive therapy and she was suspected to suffer from pulmonary aspergillosis. Oral voriconazole was initiated, and a rapid elevation of alkaline phosphatase (ALP) occurred after 4 weeks. After 2 months, the patient presented diffuse pain in bilateral skeletal regions, and bone scintigraphy revealed bilateral multiple areas of increased radiotracer uptake. We suspected the skeletal involvement as voriconazole-induced periostitis. Actually, the plasma fluoride level was increased. Voriconazole was replaced with itraconazole, and after 3 weeks, the patient stopped complaining of bone pain concomitant with the decrease in ALP. Voriconazole-induced periostitis is a rare condition but had previously been reported in solid organ or patients with bone marrow transplant who received a long-term voriconazole therapy. Our present case is distinctive of previous ones, because it occurred in a patient with connective tissue disease which had its rapid progression

Molecular Mechanism of Induction of Bone Growth by the C-Type Natriuretic Peptide

The skeletal development process in the body occurs through sequential cellular and molecular processes called endochondral ossification. Endochondral ossification occurs in the growth plate where chondrocytes differentiate from resting, proliferative, hypertrophic to calcified zones. Natriuretic peptides (NPTs) are peptide hormones with multiple functions, including regulation of blood pressure, water-mineral balance, and many metabolic processes. NPTs secreted from the heart activate different tissues and organs, working in a paracrine or autocrine manner. One of the natriuretic peptides, C-type natriuretic peptide-, induces bone growth through several mechanisms. This review will summarize the knowledge, including the newest discoveries, of the mechanism of CNP activation in bone growth

Exogenous C-type natriuretic peptide therapy for impaired skeletal growth in a murine model of glucocorticoid treatment

Growth retardation is an important side effect of glucocorticoid (GC)-based drugs, which are widely used in various preparations to treat many pediatric diseases. We investigated the therapeutic effect of exogenous CNP-53, a stable molecular form of intrinsic CNP, on a mouse model of GC-induced growth retardation. We found that CNP-53 successfully restored GC-induced growth retardation when both dexamethasone (DEX) and CNP-53 were injected from 4 to 8 weeks old. Notably, CNP-53 was not effective during the first week. From 4 to 5 weeks old, neither CNP-53 in advance of DEX, nor high-dose CNP-53 improved the effect of CNP. Conversely, when CNP-53 was started at 5 weeks old, final body length at 8 weeks old was comparable to that when CNP-53 was started at 4 weeks old. As for the mechanism of resistance to the CNP effect, DEX did not impair the production of cGMP induced by CNP. CNP reduced Erk phosphorylation even under treatment with DEX, while CNP did not changed that of p38 or GSK3β. Collectively, the effect of CNP-53 on GC-induced growth retardation is dependent on age in a mouse model, suggesting adequate and deliberate use of CNP would be effective for GC-induced growth retardation in clinical settings

Skeletal analysis of the long bone abnormality (lbab/lbab) mouse, a novel chondrodysplastic C-type natriuretic peptide mutant.

Long bone abnormality (lbab/lbab) is a strain of dwarf mice. Recent studies revealed that the phenotype is caused by a spontaneous mutation in the Nppc gene, which encodes mouse C-type natriuretic peptide (CNP). In this study, we analyzed the chondrodysplastic skeletal phenotype of lbab/lbab mice. At birth, lbab/lbab mice are only slightly shorter than their wild-type littermates. Nevertheless, lbab/lbab mice do not undergo a growth spurt, and their final body and bone lengths are only ~60% of those of wild-type mice. Histological analysis revealed that the growth plate in lbab/lbab mice, especially the hypertrophic chondrocyte layer, was significantly thinner than in wild-type mice. Overexpression of CNP in the cartilage of lbab/lbab mice restored their thinned growth plate, followed by the complete rescue of their impaired endochondral bone growth. Furthermore, the bone volume in lbab/lbab mouse was severely decreased and was recovered by CNP overexpression. On the other hand, the thickness of the growth plate of lbab/+ mice was not different from that of wild-type mice; accordingly, impaired endochondral bone growth was not observed in lbab/+ mice. In organ culture experiments, tibial explants from fetal lbab/lbab mice were significantly shorter than those from lbab/+ mice and elongated by addition of 10(-7) M CNP to the same extent as lbab/+ tibiae treated with the same dose of CNP. These results demonstrate that lbab/lbab is a novel mouse model of chondrodysplasia caused by insufficient CNP action on endochondral ossification

Evaluation of image quality of pituitary dynamic contrast-enhanced MRI using time-resolved angiography with interleaved stochastic trajectories (TWIST) and iterative reconstruction TWIST (IT-TWIST)

Background: Time‐resolved angiography with interleaved stochastic trajectories (TWIST) is a keyhole imaging with frequent sampling of central k‐space data and view‐sharing for the peripheral k‐space of dynamic phases. IT‐TWIST is a technique to reconstruct images with a smaller temporal footprint using the same raw data obtained with TWIST by iterative reconstruction. Purpose: To compare image quality between TWIST and IT‐TWIST in 3D pituitary DCE‐MRI. Study Type: Retrospective observation study. Population: Fifty‐one patients (23 men, 28 women) who underwent 3D pituitary DCE‐MRI using TWIST between July 2016 and April 2017. Field Strength/Sequence: 3T/TWIST and IT‐TWIST. Assessment: Visual evaluation was conducted for image quality of delineation of the pituitary stalk and posterior lobe during the early arterial phase, cerebral white matter near the sella turcica, and the mass lesion. Bolus sharpness of the pituitary stalk, posterior lobe, and bilateral cavernous sinus was evaluated on the enhancement slope map calculated from TWIST and IT‐TWIST. Temporal stability of intensity of the nonenhanced area was evaluated on temporal standard deviation (SD) maps calculated from TWIST and IT‐TWIST. Statistical Tests: Paired t‐test or Wilcoxon rank‐sum test was used to test the differences between TWIST and IT‐TWIST in both visual evaluation and region of interest evaluation. Results: Scores of visual evaluations for IT‐TWIST were significantly better than those for TWIST (P < 0.001) in all items. Enhancement slope for IT‐TWIST was significantly higher than that for TWIST in posterior lobe, and right and left cavernous sinus (P < 0.001). Temporal SD for IT‐TWIST was significantly lower than that for TWIST in all items, with statistical significance (P < 0.001). Data Conclusion: IT‐TWIST yielded better visualization, and better enhancement slope, and less temporal SD compared with TWIST in 3D pituitary DCE‐MRI

The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth.

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