Matrix remodeling during endochondral ossification

Abstract

Endochondral ossification, the process by which most of the skeleton is formed, is a powerful system for studying various aspects of the biological response to degraded extracellular matrix (ECM). In addition, the dependence of endochondral ossification upon neovascularization and continuous ECM remodeling provides a good model for studying the role of the matrix metalloproteases (MMPs) not only as simple effectors of ECM degradation but also as regulators of active signal-inducers for the initiation of endochondral ossification. The daunting task of elucidating their specific role during endochondral ossification has been facilitated by the development of mice deficient for various members of this family. Here, we discuss the ECM and its remodeling as one level of molecular regulation for the process of endochondral ossification, with special attention to the MMPs.In the past decade, multiple discoveries have facilitated our understanding of skeletal development. Transcription factors and/or growth factors that are involved in the genetic and molecular control of OSTEOGENESIS (see glossary box), CHONDROGENESIS and joint formation have been identified and their pathways partially elucidated [1]. The attention now turns to a different level of molecular regulation -that provided by the extracellular matrix (ECM) of the developing bone and the proteases that remodel it. Recent studies attest to the importance of unique composition of distinct ECMs within the developing skeleton, as well as their influence on cell differentiation and function [2][3][4].Bone develops in two different ways. Mesenchymal cells can directly differentiate into bone by the process of INTRAMEMBRANOUS OSSIFICATION, which is responsible for the formation of most of the craniofacial skeleton. Alternatively, these cells can differentiate into cartilage, which then provides a template for bone morphogenesis by the process of ENDOCHONDRAL OSSIFICATION; this process is responsible for the formation of most of the vertebrate appendicular and axial skeleton ( Figure 1a). Endochondral ossification occurs at two distinct sites in the vertebrate long bone -the primary (diaphyseal) and the secondary (epiphyseal) sites of ossification. Bone development initiates at the primary site. The secondary (epiphyseal) site is under independent control and is ossified later (Figure 1b). During this process, a new structure, the GROWTH PLATE, is formed between the DIAPHYSIS and the EPIPHYSIS by the segregation of CHONDROCYTES at different stages of differentiation. Under the control of signaling through Indian hedgehog (Ihh), bone morphogenetic proteins (BMPs) and fibroblast growth factor 18, a region of resting chondrocytes feeds into a zone of proliferating chondrocytes that then undergo hypertrophy and subsequently apoptosis. The ECM produced by and surrounding the terminally differentiated hypertrophic chondrocytes is calcified, partially degraded by the hypertrophic chondrocytes themselves [5], as well as by CHONDROCLASTS and/or preosteoclasts, and be...

Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3

“…The remaining bones of the axial and appendicular skeleton are produced through endochondral ossification. Skeletal elements formed through the endochondral process require the formation of an intermediate cartilaginous scaffold from which the future ossified bone will be derived (5,6).…”

In vivo delivery of fluoresceinated dextrans to the murine growth plate: Imaging of three vascular routes by multiphoton microscopy

“…As in any cellular growth system, nutrients are required to sustain the process, and multiple endocrine and paracrine inputs regulate at each stage. For growth plate cartilage, the role of the extracellular matrix also must be considered, not only as a substantive contributor to elongation per se, but through its potential role as a communication link among chondrocytes of the growth plate, and between growth plate chondrocytes and cells of surrounding tissues such as the peri-chondrium and adjacent bone (Farnum and Wilsman, 2002;Okazaki and Sandell, 2004;Ortega et al, 2004).…”

Hybrid extracellular matrix design for cartilage‐mediated bone regeneration

“…The chondrogenic aggregates terminally differentiate into hypertrophic chondroblasts which in turn form a mineralized matrix and release matrix metalloproteinase (MMP-13) and angiogenic growth factor (VEGF). [13][14][15][16] During the early stages, small proteoglycans are rapidly up-regulated to initiate ESCs condensation, while in later stages, hyaluronan (HA) is produced by chondrocytes. [17][18][19] The goal of this work was to design a hydrogel system that can guide and support human bone mesenchymal stem cells (hBMSCs) through hypertrophic-cartilage template formation.…”