Spag17 Deficiency Results in Skeletal Malformations and Bone Abnormalities

Authors

Maria Eugenia Teves, Virginia Commonwealth UniversityFollow
Gobalakrishnan Sundaresan, Virginia Commonwealth UniversityFollow
David J. Cohen, Virginia Commonwealth UniversityFollow
Sharon L. Hyzy, Virginia Commonwealth UniversityFollow
Illya Kajan, Virginia Commonwealth UniversityFollow
Melissa Maczis, Virginia Commonwealth UniversityFollow
Zhibing Zhang, Virginia Commonwealth UniversityFollow
Richard M. Costanzo, Virginia Commonwealth UniversityFollow
Jamal Zweit, Virginia Commonwealth UniversityFollow
Zvi Schwartz, Virginia Commonwealth UniversityFollow
Barbara` D. Boyan, Virginia Commonwealth UniversityFollow
Jerome F. Strauss III, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2015

Journal/Book/Conference Title

PLoS ONE

Volume

10

Issue

5

DOI of Original Publication

10.1371/journal.pone.0125936

Comments

Originally published at http://dx.doi.org/10.1371/journal.pone.0125936

Date of Submission

November 2015

Abstract

Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area and the ratio of bone area to total area, leading to reductions in the ratio of marrow area/total area in the femur. Micro-CTs and von Kossa staining demonstrated increased mineral in the femur. Moreover, osteocalcin and osterix were more highly expressed in mutant mice than in wild-type mice femurs. These data suggest that femur bone shortening may be due to premature ossification. On the other hand, tibias appear to be shorter due to a delay in cartilage and bone development. Morphometric studies showed reduction in growth plate and bone formation. These defects did not affect bone mineralization, although the volume of primary bone and levels of osteocalcin and osterix were higher. Other skeletal malformations were observed including fused sternebrae, reduced mineralization in the skull, medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from knockout mice were shorter and fewer cells had primary cilia in comparison to cells from wild-type mice. In addition, Spag17 knockdown in wild-type MEFs by Spag17 siRNA duplex reproduced the shorter primary cilia phenotype. Our findings disclosed unexpected functions for Spag17 in the regulation of skeletal growth and mineralization, perhaps because of its role in primary cilia of chondrocytes and osteoblasts.

Rights

Teves, M. E., Sundaresan, G., & Cohen, D. J., et al. Spag17 Deficiency Results in Skeletal Malformations and Bone Abnormalities. PLoS ONE, 10, e0125936. Copyright © 2015 Teves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Obstetrics and Gynecology Publications