Endochondral ossification: How cartilage is converted into bone in the developing skeleton

Abstract

Endochondral ossification is the process by which the embryonic cartilaginous model of most bones contributes to longitudinal growth and is gradually replaced by bone. During endochondral ossification, chondrocytes proliferate, undergo hypertrophy and die; the cartilage extracellular matrix they construct is then invaded by blood vessels, osteoclasts, bone marrow cells and osteoblasts, the last of which deposit bone on remnants of cartilage matrix. The sequential changes in chondrocyte behaviour are tightly regulated by both systemic factors and locally secreted factors, which act on receptors to effect intracellular signalling and activation of chondrocyte-selective transcription factors. Systemic factors that regulate the behaviour of chondrocytes in growth cartilage include growth hormone and thyroid hormone, and the local secreted factors include Indian hedgehog, parathyroid hormone-related peptide, fibroblast growth factors and components of the cartilage extracellular matrix. Transcription factors that play critical roles in regulation of chondrocyte gene expression under the control of these extracellular factors include Runx2, Sox9 and MEF2C. The invasion of cartilage matrix by the ossification front is dependent on its resorption by members of the matrix metalloproteinase family, as well as the presence of blood vessels and bone-resorbing osteoclasts. This review, which places an emphasis on recent advances and current areas of debate, discusses the complex interactions between cell types and signalling pathways that govern endochondral ossification.

Introduction

Most bones develop through a process known as endochondral ossification, the initial stage of which is the formation of a cartilage model. During foetal development and postnatal growth, this model is gradually replaced by bone. Cartilage models are formed through condensation of mesenchymal cells, followed by their differentiation into chondrocytes and secretion of typical cartilage extracellular matrix components (Fig. 1A). The cartilage model once formed is invaded first at its centre and later at each end by a mixture of cells that establish the primary and secondary (respectively) centres of ossification (Fig. 1B–D). These centres of ossification gradually encroach on the remaining cartilage, ultimately replacing it completely (except at the articular surfaces) by the time skeletal maturity is achieved (Fig. 1E). The importance of the cartilage model lies not only in its provision of a mechanically stable template for bone formation, but also in its role as the source of longitudinal bone growth. The dynamic events that occur in growth cartilage leading to its replacement by bone will be the subject of this review. A number of recent reviews have described the roles of specific groups of molecules in endochondral ossification; the aim of this review is to provide an overview of the complex molecular and cellular interactions underlying the process of endochondral ossification, with an emphasis on recent advances and current areas of debate.