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THE FATE OF THE TERMINALLY DIFFERENTIATED CHONDROCYTE: EVIDENCE FOR MICROENVIRONMENTAL REGULATION OF CHONDROCYTE APOPTOSIS

Department of Orthopaedic Surgery, Thomas Jefferson Medical College, 1015 Walnut Street, 501, Philadelphia, PA 19107;

View larger version (158K): [in a new window]   Figure 1. Organization of the mammalian growth plate. The growth plate is classically divided into four major zones. The approximate extent of each of these regions is shown in this longitudinal section of a rat growth plate. The most superficial zone, resting cartilage, contains chondroprogenitor cells. These cells serve as the stem chondrocytes or chondroblasts of the growth plate. In the proliferative cartilage zone, chondrocytes divide rapidly in a direction that is parallel to the long axis of the bone, thereby providing longitudinal appositional growth. In the hypertrophic cartilage zone, chondrocytes cease to divide and begin to increase their intracellular volume, therefore achieving some interstitial growth. Toward the bottom of the growth plate, the hypertrophic chondrocytes induce calcification of the extracellular matrix. It is in this zone that apoptotic cells are evident.

View larger version (97K): [in a new window]   Figure 2. Schematic of common pathways that can lead to apoptosis. Apoptosis can be activated in two ways: First, at the plasma membrane, a ligand must be bound to a death receptor to activate apoptosis. Binding leads to oligomerization of the receptors, recruitment of an adaptor protein, and activation of FADD. Caspase-8 is then bound to this death complex and activated. This enzyme then binds and activates caspase-3, the executioner caspase, which then activates Caspase-Activated Deoxyribonucleases (CAD). These enzymes are responsible for degrading chromatin and generating the DNA fragments that are characteristic of apoptosis. CADs have their own inhibitor, appropriately named Inhibitors of Caspase-Activated Deoxyribonucleases (ICADs). The second pathway requires that apoptogens enter the cell and stimulate synthesis and activation of Bax and Bid, two pro-apoptotic members of the Bcl-2 family, while inhibiting or inactivating Bcl-2 and Bcl-x, two anti-apoptotic proteins. Removal of Bcl-2 from the mitochondrial membrane causes a decrease in the mitochondrial membrane potential (m) and the generation of a mitochondrial membrane permeability transition (MMPT). When this occurs, there is release of cytochrome c, APAF-1, and other proteins from the intramembrane space to form an apoptosome that binds procaspase-9. Caspase 9 then activates caspase-3, which then goes on to cause the nuclear changes described above. Mitochondria release yet another protein, Smac/Diablo. This protein promotes caspase activation by associating with the apoptosome and inhibiting the activity of another set of proteins, the IAPs (Inhibitor of Apoptosis Proteins). These proteins bind to and inhibit caspase-9 and thereby block the apoptotic process. The MMPT also causes other cellular changes. Thus, there is generation of Reactive Oxygen Radicals (ROS) which lower the thiol reserve (GSH) of the cell. There is also activation of Nitric Oxide Synthase enzymes (NOS) which release Nitric Oxide (NO) from arginine. NO and ROS can activate caspases and cause loss of cell viability.

View larger version (86K): [in a new window]   Figure 3. A schematic of biochemical changes in the maturing chondrocyte that are linked to the initiation of apoptosis. We hypothesize that, during early maturation, mitochondrial function is normal. As the cells mature, the mitochondria experience a mitochondrial membrane permeability transition (MMPT) with a concomitant loss of cytochrome c and other proteins. Consequently, the mitochondrial membrane potential decreases as the cell matures. The cell is now primed for apoptosis. Once the MMPT has occurred, there is generation of ROS and a concomitant decrease in the thiol-reductive reserve. There is some evidence to indicate that, at this stage, there is a decrease in Bcl-2 expression. It is not known if this is due to the loss of mitochondrial potential, or whether it is responsible for the MMPT. There is also evidence that maturation results in caspase activation. This, too, would increase the sensitivity of hypertrophic chondrocytes to the presence of apoptogens. As indicated in the Fig., during the maturation process there is a stage when the increase in pro-apoptotic factors (Pi, Ca2+, RGD peptides, etc.) overwhelms the activity of anti-apoptotic factors, and the cells become committed to death.