Expression of bone-specific genes by hypertrophic chondrocytes: Implications of the complex functions of the hypertrophic chondrocyte during endochondral bone development

Abstract

Endochondral bone formation is one of the most extensively examined developmental sequences within vertebrates. This process involves the coordinated temporal/spatial differentiation of three separate tissues (cartilage, bone, and the vasculature) into a variety of complex structures. The differentiation of chondrocytes during this process is characterized by a progressive morphological change associated with the eventual hypertrophy of these cells. These cellular morphological changes are coordinated with proliferation, a columnar orientation of the cells, and the expression of unique phenotypic properties including type X collagen, high levels of bone, liver, and kidney alkaline phosphatase, and mineralization of the cartilage matrix. Several studies indicate that hypertrophic chondrocytes also express osteocalcin, osteopontin, and bone sialoprotein, three proteins which until very recently were widely believed to be restricted in their expression to osteoblasts. Recent studies suggest that the hypertrophic chondrocytes are regulated by the calcitropic hormones, morphogenic steroids, and local tissue factors. These considerations are based on the regulation by 1,25 (OH)2D3 and retinoids of the cartilage specific genes as well as osteopontin and osteocalcin expression in hypertrophic chondrocytes. They are also based on the effects on growth plate development caused by 1) transgenic ablation of autocrine/paracrine regulators such as PTHrP and of the transcriptional regulator c-fos and 2) naturally occurring genetic mutations of the FGF receptor. These studies further suggest that specific transcriptional factors mediate exogenous regulatory signals in a coordinated manner with the development of bone. While it has been widely demonstrated that the majority of hypertrophic chondrocytes undergo apoptosis during terminal stages of the developmental sequence, their response to specific exogenous regulatory signals and their expression of bone-specific proteins give rise to questions about whether all growth chondrocytes have the same developmental fates and have identical functions. Furthermore, specific questions arise as to whether there are similar mechanisms of regulation for commonly expressed genes found in both cartilage and bone or whether these genes have unique regulatory mechanisms in these different tissues. These recent findings suggest that hypertrophic chondrocytes are functionally coupled during endochondral bone formation to the recruitment of osteoblasts, vascular cells, and osteoclasts.

Distinct Transglutaminase 2-independent and Transglutaminase 2-dependent Pathways Mediate Articular Chondrocyte Hypertrophy

“…In addition, hypertrophic chondrocytes demonstrate altered patterns of collagen subtype generation that include stereotypic up-regulated type X collagen expression, and hypertrophic chondrocytes show markedly increased release of mineralization-competent secretory vesicles (2). In addition, hypertrophic chondrocytes demonstrate increased alkaline phosphatase (AP) activity and other alterations in the metabolism of P i and PP i (4,6). In this context, P i and PP i mediate both calcification and growth plate organization (5), and P i promotes chondrocyte hypertrophy (6).…”

“…Chondrocyte hypertrophic differentiation in both the growth plate and in OA articular cartilage has been heretofore linked closely with a state in which matrix calcification is up-regulated (2,4,8). However, it has not been clarified if there is an obligate linkage of up-regulated calcification with chondrocyte hypertrophic differentiation.…”

Modulation of extracellular matrix protein phosphorylation alters mineralization in differentiating chick limb-bud mesenchymal cell micromass cultures

“…The phosphorylated proteins synthesized by mature chick chondrocytes and present in the mineralizing chick cartilage matrix include osteopontin, bone sialoprotein, and osteonectin [43,44]. It is likely that other matrix proteins (e.g., DMP1, DSP, etc) present in the murine growth plate [45] are also present in the chick, as suggested in our unpublished microarray data.…”

The chondrogenic differentiation of mesenchymal stem cells on an extracellular matrix scaffold derived from porcine chondrocytes

“…During endochondral ossification, hypertrophic changes and calcification of matrix are known to be followed by vessel invasion [25,26]. Furthermore, gross observations of the ECM and PGA samples retrieved at 4 and 6 weeks after implantation showed more significant vessel invasion in the PGA group, as shown by the intensities of red color ( Fig.…”