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Kashin-Beck disease (KBD) is an endemic chronic osteochondral disease, which has a high prevalence and morbidity in the Eastern Siberia of Russia, and in the broad diagonal, northern-east to southern-west belt in China and North Korea. In 1990's, it was estimated that in China 1–3 million people had some degree of symptoms of the disease, although even higher estimates have been presented. In China, the extensive prevalence peaked in the late 1950's, but since then, in contrast to the global trend of the osteoarthritis (OA), the number of cases has been dramatically falling. Up to 2013, there are 0.64 millions patients with the KBD and 1.16 millions at risk in 377 counties of 13 provinces or autonomous regions. This is obviously thanks to the preventive efforts carried out, which include providing millions of people with dietary supplements and clean water, as well as relocation of whole villages in China. However, relatively little is known about the molecular mechanisms behind the cartilage damage, the genetic and the environmental risk factors, and the rationale of the preventive effects. During the last decade, new data on a cellular and molecular level has begun to accumulate, which hopefully will uncover the grounds of the disease.
The Kashin-Beck disease (KBD) includes multiple symptoms in the growth and the articular cartilages. It has been known since the sixteenth century, but the first one to describe the disease was I. M. Yurensky in 1849. Some years later (1859–1868), a doctor Nikolai Kashin also investigated the disease, and named it as the Urov disease according to the area where it was abundant. In 1906, a doctor Eugene Beck described his medical cases in a monograph Osteoarthritis Deformans Endemica. Later, the disease became known as the KBD. The research efforts on the KBD originated from Russia, then Japanese had an intense period of a research, and finally the research focus has gradually moved to China. Recently, an international collaboration has increased the awareness of the KBD also outside of Asia.
Symptoms of the KBD in the cartilage
The epiphyseal growth plate and the articular cartilage are the most commonly affected anatomical sites in the KBD patients. Microscopically, the degenerative changes in the KBD cartilage are characterized by the chondronecroses in the multiple foci of the deep zone of the cartilage [Fig. 1(J) and (K)]. The focal chondronecroses and an impaired endochondral ossification mostly result in a secondary chronic osteoarthropathy. In the fetal and the juvenile cartilage, most of the KBD changes are located at the zones of the maturing and the hypertrophic cartilage. The necrotic fields can extend to the transitional region between the proliferative and the hypertrophic zones of the growth plate cartilage and, in the advanced KBD, even to all zones of the cartilage6 . Before the overt Fig. 1. Two KBD children aged 7 (A) and 15 (B) years old manifested the deformed joints in the limbs, had especially a knee varus deformity and the shortened humeri and the stature. The flexion of the terminal finger joints or the deformed fingers (CeE) was mostly occurring first in the children. The radiographic findings in the right hand of the KBD patients aged 13 (F), and 45 (G), and the feet of 9 years old one (H), respectively. In the growth plate cartilage of the KBD children, the large chondronecrotic areas without cells were typically observed in the deep zone of the cartilage (arrows in J and K). Such findings were not seen in the control cartilage (I). The chondrocyte size was significantly reduced in the KBD (J), but the cell membranes were intact. The nuclei were dissolved, broken and compressed, and associated with a red staining in the chondrocyte cytoplasm (K), and the cellular fibrillated areas (arrowhead) appeared. In contrast to the control cartilage (L), the chondrocyte clusters and the foci of chondronecrosis, the compressed nucleus and the incomplete cell membrane appeared in the upper and the middle zone in the articular cartilage of the KBD adults (M, N). Hematoxylineeosin staining, 100 20. X. Guo et al. / Osteoarthritis and Cartilage 22 (2014) 1774e1783 1775 degenerative changes appear in the cartilage extracellular matrix, the chondrocyte necrosis can be visualized under the electron microscope7 . The chondronecrosis of the growth plate can result in a disturbed endochondral ossification, and even induce the early closure of the epiphyseal growth plate, which will lead to the growth retardation, such as the short fingers, the short limbs, the retarded growth and a disability in the advanced stages . Since the growth plate cartilage is the growth center of the bone, the developmental deformities of the KBD patients are most likely a result of an impaired chondrocyte differentiation and the endochondral ossification. The younger the symptoms arise, the more serious malformations develop. Additionally, the chondronecrosis of the articular cartilage can induce a scar formation, bony enlargements, osteophytes, loose bodies and a narrowed joint space in the KBD patients . The electron microscopic analyses have confirmed the chondrocyte necrosis and revealed a reduction in the collagen fibril diameter, and a loss of the fibril banding patterns in the cartilage matrix of the KBD patients . The KBD chondrocytes display the swollen mitochondria and a decreased density of the mitochondrial matrix compared to the normal ones . The distended cisternae and a ribosomal detachment from the membrane are present in the swollen endoplasmic reticulum after a cell injury These endoplasmic reticulum events may coincide in an apoptosis and a necrosis. Besides the distended Golgi apparatus there can be more secretory vacuoles in the KBD chondrocytes .
Besides the classical deep zone chondronecrotic changes, the chondrocyte dedifferentiation and an abnormal type X collagen, Parathyroid hormone related protein (PTHrP), transforming growth factor-b (TGF-b), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) staining patterns have been discovered in the KBD cartilage , which suggests that the endochondral ossification and the terminal differentiation disorders of the chondrocytes may be involved in the pathogenesis of the KBD. The degenerative and the hypertrophic changes have also been noticed in the KBD chondrocyte cultures . The excessive apoptosis and the abnormal expression of the apoptosis regulating factors, such as Bcl-2, Bax, Fas and inducible NO synthase (iNOS) are consistent findings with the increased serum levels of NO and the iNOS in the KBD patients. The proteoglycan metabolism is affected by the KBD, since a decreased content of the proteoglycans can be found in the deep.
zone of the cartilage, particularly in the necrotic areas. The aggrecanase-generated epitopes are present in the KBD cartilage, and also an increased serum content of CD44 and its immunostaining in the KBD cartilage. The potential markers of the joint damage, i.e., cartilage oligomeric matrix protein (COMP) and type II collagen telopeptides, are also increased in the serum. The urine concentrations of the unsaturated glycosaminoglycan disaccharides and the pyridinoline cross-links of the collagens also correlated with the grade of the KBD. The serum levels of the catabolic cytokines interleukin-1b and a tumor necrosis factor-a were high both in the normal and the KBD children in the KBD regions, suggesting that some yet unidentified factors may protect certain people from the disease. The markers of an autoimmune and an inflammatory response were also elevated in the KBD patients.
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