Fate of the hypertrophic chondrocyte: Microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate

Abstract

The goal of this review is to examine the fate of the hypertrophic chondrocyte in the epiphyseal growth plate and consider the impact of the cartilage microenvironment on cell survival and apoptosis. Early investigations pointed to a direct role of the hypertrophic chondrocyte in osteogenesis. The terminally differentiated cells were considered to undergo a dramatic change in shape, size, and phenotype, and assume the characteristics of an osteoblast. While some studies have supported the notion of transdifferentiation, much of the evidence in favor of reprogramming epiphyseal chondrocytes is circumstantial and based on microscopic evaluation of cells that are present at the chondro-osseous junction. Although these investigations provided a novel perspective on endochondral bone formation, they were flawed by the failure to consider the importance of stem cells in osseous tissue formation. Subsequent studies indicated that many, if not all, of the cells of the cartilage plate die through the induction of apoptosis. With respect to agents that mediate apoptosis, at the chondro-osseous junction, solubilization of mineral and hydrolysis of organic matrix constituents by septoclasts generates high local concentrations of ions, peptides, and glycans, and secreted matrix metalloproteins. Individually, and in combination, a number of these agents serve as potent chondrocyte apoptogens. We present a new concept: hypertrophic cells die through the induction of autophagy. In the cartilage microenvironment, combinations of local factors cause chondrocytes to express an initial survival phenotype and oxidize their own structural macromolecules to generate ATP. While delaying death, autophagy leads to a state in which cells are further sensitized to changes in the local microenvironment. One such change is similar to ischemia reperfusion injury, a condition that leads to tissue damage and cell death. In the growth cartilage, an immediate effect of this type of injury is sensitization to local apoptogens. These two concepts (type II programmed cell death and ischemia reperfusion injury) emphasize the importance of the local microenvironment, in particular pO(2), in directing chondrocyte survival and apoptosis.

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

“…Studies showing the presence of apoptotic nuclei in HCs and abundant apoptogens in the microenvironment of HCs at the chondro-osseous junction provided the current concept that death, by apoptosis or extended autophagy, is the fate of HCs in endochondral ossification (12,22). However, these studies cannot preclude that some HCs survive.…”

“…The possibility that HCs are an alternative source of osteoblasts is controversial (12). Support comes from imaging, morphological, and ultrastructural studies in vivo, in which HCs were observed at the chondro-osseous junction and osteoblasts in chondrocyte lacuna (13)(14)(15)(16)(17)(18).…”

“…Support comes from imaging, morphological, and ultrastructural studies in vivo, in which HCs were observed at the chondro-osseous junction and osteoblasts in chondrocyte lacuna (13)(14)(15)(16)(17)(18). Recent lineage studies failed to resolve this issue because non-HC-specific reagents were used to track the fate of HCs (2,19,20) or because the half-life of fluorescent protein tracers in HCs may not be sufficient to span a possible HC-to-osteoblast transition (21).Studies showing the presence of apoptotic nuclei in HCs and abundant apoptogens in the microenvironment of HCs at the chondro-osseous junction provided the current concept that death, by apoptosis or extended autophagy, is the fate of HCs in endochondral ossification (12,22). However, these studies cannot preclude that some HCs survive.…”

Autophagy Prior to Chondrocyte Cell Death During the Degeneration of Meckel's Cartilage

“…During the process of cell death, chondrocytes become hypertrophic and terminally differentiated. In addition, with the degradation of extracellular matrices, chondrocytes die and disappear (Shapiro et al, 2005;Sakakura et al, 2007). Compared with the degeneration of Meckel's cartilage, more studies were conducted on endochondral ossification.…”

Chondrocytes Embedded in the Epiphyseal Growth Plates of Long Bones undergo Autophagy Ppior to the Induction of Osteogenesis

“…1 A reason for considering that the cells exhibit autophagy, is that in the maturing zone of the growth plate, the central core of cells are most removed from oxygen and may be depleted of growth factors and critical nutrients. Some early analytical studies of the growth plate provide evidence in support of this notion.…”