Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation
Article first published online: 28 MAR 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 4, pages 831–840, April 2014
How to Cite
Dittmann, K., Wuelling, M., Uhmann, A., Dullin, C., Hahn, H., Schweyer, S., Vortkamp, A. and Wienands, J. (2014), Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation. Arthritis & Rheumatology, 66: 831–840. doi: 10.1002/art.38325
- Issue published online: 28 MAR 2014
- Article first published online: 28 MAR 2014
- Accepted manuscript online: 24 DEC 2013 08:00AM EST
- Manuscript Accepted: 12 DEC 2013
- Manuscript Received: 8 FEB 2013
- DFG through TRR130, project 08
During development of the vertebrate skeleton, chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (HH) family have been implicated in the ossification process, but their exact relationship to normal or pathogenic bone formation is unclear. This study was undertaken to establish a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and to investigate in vivo how chondrocyte-specific ablation of the inhibitory HH receptor Patched 1 (Ptch1) affects skeleton integrity.
A Cre-deleter mouse strain, mb1-Cre, for selective gene recombination in spinal chondrocytes was identified by in situ hybridization and histologic analysis. The mb1-Cre+/− animals were crossed with mice that harbor a loxP-flanked Ptch1 gene (Ptch1flox/flox) to abrogate the inhibition of the HH signaling pathway in chondrocytes. The skeletal integrity of F1 mice was characterized by high-resolution flat-panel–based volume computed tomography and histologic staining procedures.
During the first weeks after birth, all mb1-Cre+/−/Ptch1flox/flox mice developed progressive spinal fusion with malformation of the vertebrae. This phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner.
Our findings indicate that chronic activation of the HH signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin.