Transforming growth factor alpha controls the transition from hypertrophic cartilage to bone during endochondral bone growth

We have recently identified transforming growth factor alpha (TGF alpha) as a novel growth factor involved in the joint disease osteoarthritis. The role of TGFa in normal cartilage and bone physiology however, has not been well defined. Purpose: The objective of this study was to determine the role of TGF alpha in bone development through investigation of the Tgfa knockout mouse. Methods: The gross skeletons as well as the cartilage growth plates of Tgfa knockout mice and their control littermates were examined during several developmental stages ranging from newborn to ten weeks old. Results: Knockout mice experienced skeletal growth retardation and expansion of the hypertrophic zone of the growth plate. These phenotypes were transient and spontaneously resolved by ten weeks of age. Tgfa knockout growth plates also had fewer osteoclasts along the cartilage/bone interface. Furthermore, knockout mice expressed less RUNX2, RANKL, and MMP13 mRNA in their cartilage growth plates than controls did. Conclusions: Tgfa knockout mice experience a delay in bone development, specifically the conversion of hypertrophic cartilage to true bone. The persistence of the hypertrophic zone of the growth plate appears to be mediated by a decrease in MMP13 and RANKL expression in hypertrophic chondrocytes and a resulting reduction in osteoclast recruitment. Overall, TGFa appears to be an important growth factor regulating the conversion of cartilage to bone during the process of endochondral ossification. (C) 2012 Elsevier Inc. All rights reserved.