Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritic human articular knee cartilage: A study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage

Abstract

Objective Chondrocytes are crucial for adequate matrix balance and function. Cell proliferation and, recently, extensive apoptotic cell death have been reported in osteoarthritic (OA) cartilage. Apoptotic cell death would be an obvious central factor in the initiation and progression of OA, since there is no potential for replacing articular chondrocytes in the adult. Therefore, we studied the occurrence of apoptotic cell disintegration and cell proliferation in OA and normal articular cartilage obtained from the knees of adult donors of all ages. Methods Following immunostaining for cellular proteins as well as staining for nuclear DNA, we performed triple‐channel confocal laser scanning microscopy on thick cartilage slices to evaluate lacunar emptying and cell viability. Cell proliferation and apoptotic cell death were evaluated morphologically, by immunodetection of the proliferation‐associated Ki‐67 antigen, and by the TUNEL reaction. Results With the exception of the calcified layer, we were not able to detect any major (apoptotic or nonapoptotic) cell disintegration in normal young or aged articular knee cartilage. Single apoptotic cells were detected in OA articular knee cartilage. A significant increase in lacunar emptying was observed in late‐stage specimens with higher Mankin scores compared with age‐matched normal control cartilage specimens, but not in low‐grade lesions. A significant (but lesser) increase in empty lacunae was also observed with age in normal cartilage. Cell proliferation was rarely detected in OA cartilage samples and was not detected at all in normal cartilage samples. Conclusion Our results confirm the findings of previous studies showing that cell proliferation occurs in OA cartilage. They also show that, contrary to previous suggestions, apoptotic cell death is not a widespread phenomenon in aging or OA cartilage.

Cilostazol protects rat chondrocytes against nitric oxide–induced apoptosis in vitro and prevents cartilage destruction in a rat model of osteoarthritis

“…Although apoptotic chondrocyte death is not always a widespread phenomenon in cartilage aging or OA cartilage degeneration (38), obviously any kind of cell death is detrimental to the tissue. Therefore, any strategy to prevent chondrocyte death or to manipulate the mechanism mediated by stimuli that cause cell death has potential for substantial therapeutic impact (39).…”

Cartilage tissue engineering for degenerative joint disease☆

“…Although several studies have demonstrated a high rate of apoptosis upon mechanical trauma [41], the role of apoptosis in OA remains controversial [42,43]. While some studies indicated increased rates of apoptosis in OA, linked to proteoglycan depletion from the ECM [44,45], others have shown increased apoptosis only in the calcified cartilage layer [46].…”

Ontogeny of rat chondrocyte proliferation: studies in embryo, adult and osteoarthritic (OA) cartilage

“…Other markers of cell proliferation such as PCNA, which is an S phase marker, can also be detected during DNA replication and repair, and therefore are not specific for cell division. Ki-67, another cell proliferation marker, is present during the entire cell cycle; its concentration and/ or localization changes during mitotic phases [4,5,11,12], which is when chromosomes are observed and mitosis can therefore be detected. Consequently, the presence of Ki-67 is not necessarily indicative of cell division if it is not associated with chromosomes.…”