Inactivation of patched1 in murine chondrocytes causes spinal fusion without inflammation.
OBJECTIVE
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.


METHODS
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 (Ptch1(flox/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.


RESULTS
During the first weeks after birth, all mb1-Cre(+/-) /Ptch1(flox/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.


CONCLUSIONS
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.
Georg August University of Göttingen, Göttingen, Germany.
Kai
K
Dittmann
Manuela
M
Wuelling
Anja
A
Uhmann
Christian
C
Dullin
Heidi
H
Hahn
Stefan
S
Schweyer
Andrea
A
Vortkamp
Jürgen
J
Wienands
D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000502:physiology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface