Epidermal Growth Factor Receptor-deficient Mice Have Delayed Primary Endochondral Ossification Because of Defective Osteoclast Recruitment

Ke Wang,Hiroaki Yamamoto,Jennie R Chin,Zena Werb,Thiennu H Vu

doi:10.1074/jbc.m403114200

Ke Wang, Hiroaki Yamamoto + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m403114200

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Abstract

The epidermal growth factor receptor (EGFR) and its ligands function in diverse cellular functions including cell proliferation, differentiation, motility, and survival. EGFR signaling is important for the development of many tissues, including skin, lungs, intestines, and the craniofacial skeleton. We have now determined the role of EGFR signaling in endochondral ossification. We analyzed long bone development in EGFR-deficient mice. EGFR deficiency caused delayed primary ossification of the cartilage anlage and delayed osteoclast and osteoblast recruitment. Ossification of the growth plates was also abnormal resulting in an expanded area of growth plate hypertrophic cartilage and few bony trabeculae. The delayed osteoclast recruitment was not because of inadequate expression of matrix metalloproteinases, including matrix metalloproteinase-9, which have previously been shown to be important for osteoclast recruitment. EGFR was expressed by osteoclasts, suggesting that EGFR ligands may act directly to affect the formation and/or function of these cells. EGFR signaling regulated osteoclast formation. Inhibition of EGFR tyrosine kinase activity decreased the generation of osteoclasts from cultured bone marrow cells.

Highlights

Skeletal elements develop by two distinct mechanisms: intramembranous and endochondral ossification [1]
At E18.5, the EGFRϪ/Ϫ humeri showed a lengthened hypertrophic cartilage (HC) zone at the growth plate and ossification that had not proceeded very far longitudinally (Fig. 1D). This delay in ossification continued until birth, with continuing accumulation of HC at the growth plates in newborn EGFRϪ/Ϫ mice compared with their wild type or heterozygous littermates (Fig. 1, E and F)
We concluded that primary ossification of the cartilage templates and the subsequent ossification of the growth plates of the long bones are impaired in the EGFRϪ/Ϫ mice

Summary

Introduction

Skeletal elements develop by two distinct mechanisms: intramembranous and endochondral ossification [1]. Primary ossification in the wild type and EGFRϩ/Ϫ bones occurred normally with humeri at E16.5 showing completed invasion of capillaries into the calcified hypertrophic cartilage (HC), with the resultant removal of the middle section of the HC and replacement of this area with vascularized tissues (Fig. 1A). At E18.5, ossification in the wild type/heterozygous humeri continued in the longitudinal direction resulting in the formation of an area of trabecular bone (primary spongiosa) and a growth plate that contained an area of hypertrophic cartilage of relatively small size (Fig. 1C).

Results

Conclusion