FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease
- David M. Ornitz1,3 and
- Pierre J. Marie2
- 1Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA; 2Laboratory of Osteoblast Biology and Pathology, INSERM U349 affiliated CNRS, Hopital Lariboisiere, Paris cedex 10, France
This extract was created in the absence of an abstract.
Over the last decade the identification of mutations in the receptors for fibroblast growth factors (FGFs) has defined essential roles for FGF signaling in both endochondral and intramembranous bone development. FGF signaling pathways are essential for the earliest stages of limb development and throughout skeletal development. In this review, we examine the role of FGF signaling in bone development and in human genetic diseases that affect bone development. We also explore what is presently known about how FGF signaling pathways interact with other major signaling pathways that regulate chondrogenesis and osteogenesis.
Overview of skeletal development
Skeletal elements are formed through two distinct developmental processes. Endochondral ossification gives rise to long bones that comprise the appendicular skeleton, facial bones, vertebrae, and the lateral medial clavicles. Intramembranous ossification gives rise to the flat bones that comprise the cranium and medial clavicles. Both types of ossification involve an initial condensation of mesenchyme and the eventual formation of calcified bone. However, intramembranous bone formation accomplishes this directly, whereas endochondral ossification incorporates an intermediate step in which a cartilaginous template regulates the growth and patterning of the developing skeletal element.
Development of endochondral bones initiates shortly after the formation of the limb bud with the condensation of loose mesenchyme, marked by expression of type II collagen (Fig. 1A;Kosher et al. 1986; Nah et al. 1988). Condensing mesenchyme forms an anlage for the endochondral skeleton and can either branch or segment to form individual skeletal elements (Hall and Miyake 1992, 2000). Differentiation of condensing mesenchyme gives rise to a proliferating population of centrally localized type II collagen-expressing chondrocytes and more peripherally localized type I collagen-expressing perichondrial cells (Kosher et al. 1986). At this stage, chondrocytes begin to elaborate a specialized extracellular matrix containing type II collagen. Midway between the ends of this elongated cartilaginous template, chondrocytes …
