Patched1

Inactivation of Patched 1 in chondrocytes causes spinal fusion without inflammation.

"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.  During the first weeks after birth all mb1-Cre+/- /Ptch1flox/flox mice developed a progressive spinal fusion with malformation of the vertebrae. The aclampsia 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. 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. "

"Ligation of Ptch1 releases its inhibition of the transmembrane signaling partner Smoothened (Smo), which in turn activates intracellular signaling cascades, most notably through activation of transcription factors of the Gli family"

"Compared with wild-type mice, the tail vertebrae of Ptch1 mutants were much shorter, irregularly shaped and severely lacerated"

"These experiments revealed massive proliferation of chondrocytes and an abnormal growth plate with an absence of hypertrophic chondrocytes in the hyperproliferative cell fraction[in Ptch1 mutants]. Furthermore, staining with Safranin/Weigert to discriminate between bone and cartilage revealed the presence of proliferating chondrocytes in the intervertebral discs and a marked loss of fibrous cartilage,"<-So excess chondrocyte proliferation doesn't increase height if it comes at the expense of chondrocyte proliferation.  Maybe height would be greater if chondrocyte hypertrophy was induced after excess chondrocyte proliferation.

"The nucleus pulposus seemed to be displaced by the proliferating chondrocytes. Importantly, no infiltration of leukocytes could be detected.  These data demonstrated ongoing chondrocyte proliferation in the intervertebral discs of adult Ptch1 mutants, which in turn blocked chondrocyte maturation and proper endochondral ossification."

"Chronic activation of the chondrocytic Hh pathway following Ptch1 ablation suffices to induce spinal fusion without aberrant activation of the immune system."

"In the growth plate of the limbs, forced expression of either Shh or Ihh activates chondrocyte proliferation and impairs joint formation. In the lumbar spine, chondrocyte proliferation and hedgehog responsiveness measured by a Gli1 reporter ceases during aging. Importantly, proliferation is abolished after 3 weeks postnatally"