Proteoglycan metabolism, cell death and Kashin-Beck disease

Abstract

Kashin-Beck Disease (KBD) is an endemic, chronic and degenerative osteoarthropathy principally occurring in children. The characteristic pathological change of KBD is chondrocyte necrosis in hyaline articular cartilage. Proteoglycans are one of the major components in the extracellular matrix of articular cartilage, and disrupted proteoglycan metabolism and loss of proteoglycans in articular cartilage from KBD patients has been observed. In this mini-review, we discuss the close relationship between chondrocyte death including necrosis and loss of proteoglycan, and its potential mechanism during KBD onset and development, which may provide new clues for KBD research.

Fig. 1

Schematic demonstration of aggrecan degradation. The domain structure of aggrecan core protein with different regions is shown. G1, 2 and 3 are the globular domains, IGD is the interglobular domain, KS, CS-1 and CS-2 are the glycosaminoglycan (keratan sulfate and chondroitin sulfate) attachment regions. Proteolytic cleavage sites on the core protein of aggrecan are displayed by black arrows. The blue number in hexagon denotes the preferred order of cleavage

Fig. 2

Aggrecan immunohistochemical staining in articular cartilage from rat KBD animal model. KBD rat model was produced by administration with T-2 toxin and selenium deficiency food for 4 weeks. a aggrecan positive staining evenly distributes across the whole section of articular cartilage from control group. b Focal depletion of aggrecan staining (hollow black arrows) was observed in the articular cartilage from T-2 toxin and selenium deficiency group. The area enclosed with back square was magnified and displayed in c, note the depletion of aggrecan staining in pericellular matrix of a single chondrocyte (black arrow), and the chondrocyte cluster formation and its strong aggrecan staining adjacent to the focal proteoglycan loss area (hollow red arrow). Scale Bar: 50 μm

Fig. 3

Immunostaining for chondroitin sulphate (CS)/dermatan sulphate (DS) expression in articular cartilage from KBD animal model. KBD rat model was produced by administration with T-2 toxin and selenium deficiency food for 4 weeks. The expression of different epitopes (6C3 and 7D4) along CS/DS chains on proteoglycans in articular cartilage was investigated using immunohistochemical staining (red colour). 6C3 and 7D4 positive staining is mainly localised in the pericellular matrix. In the articular cartilage from control group, 6C3 and 7D4 positive staining is observed in all layers, although the most of the intensive staining is in the superficial and middle zone. In contrast, there is no or very weak 6C3 and 7D4 positive staining in middle and deep zones of articular cartilage from low selenium diet plus T-2 toxin (KBD model group). Interestingly, much stronger positive staining of 6C3 and 7D4 epitopes is observed in the superficial zone of articular cartilage from KBD model group. These results indicate the alteration of CS/DS metabolism induced by selenium deficiency nutrition and T-2 toxin. Scale Bar: 50 μm