Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis, the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts, which suggests that the defect directly interferes with osteoclast differentiation. In other mutants, it is the function of the osteoclast that seems to be affected, as they show normal or elevated numbers of non-functioning osteoclasts. Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.

Objective-We investigated the potential role of ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motif type I) in atherogenesis. Methods and Results-ADAMTS-1 is expressed at the highest levels in the aorta when compared with other human tissues examined. Immunolocalization studies in human aorta and coronary artery indicate that ADAMTS-1 expression is mainly seen at low levels in the medial layer, but upregulated in the intima when plaque is present. We found that ADAMTS-1 mRNA levels are significantly higher in proliferating/migrating cultured primary aortic vascular smooth muscle cells (VSMCs) compared with resting/confluent cells. Using the mouse carotid artery flow cessation model, we show that there are differences in vessel remodeling in ADAMTS-1 transgenic/apoE-deficient mice compared with apoE deficiency alone, particularly a significant increase in intimal hyperplasia. We show that ADAMTS-1 can cleave the large versican containing proteoglycan population purified from cultured human aortic VSMCs. Finally, using versican peptide substrates, we show data suggesting that ADAMTS-1 cleaves versican at multiple sites. Conclusion-We See page 12Early in atherogenesis, VSMCs from the media are thought to migrate into the intima and contribute to the development of atherosclerotic lesions. Although what initially triggers these events is not known, it is thought that proteases released by VSMCs degrade the matrix proteins in the intima, particularly the main proteoglycan of the arterial intima versican, making the intima more permissive for invasion by VSMCs. One recently discovered family of metalloproteases, the ADAMTS family, might play a key role in atherogenesis by modulating the degradation of versican and possibly other proteoglycans.The first member of this family to be identified is ADAMTS-1. 3,4 It has been observed that ADAMTS-1 mRNA is upregulated substantially in human umbilical vein endothelial cells and cardiac microvascular endothelial cells under shear stress, suggesting regulation during flow-dependent vascular remodeling. 5 ADAMTS-1 has been shown to cleave the proteoglycan versican, which is expressed by VSMCs. 6 -8 Versican can exist in 4 isoforms (V0, V1, V2, and V3), depending on alternative splicing of the chondroitin sulfate containing glycosaminoglycan domains. V0 versican contains all possible domains, whereas the glycosaminoglycan-alpha and glycosaminoglycan-beta domains are spliced out in the V1 and V2 versican isoforms, respectively. 7 ADAMTS-1 and ADAMTS-4 have been shown to cleave V1/V0 versican at the Glu 441 -Ala 442 /Glu 1428 -Ala 1429 bond and the product of this cleavage was shown to be present in human atherosclerotic plaques by immunohistochemistry using neoepitope antibodies. 8 ADAMTS-1 has also been shown to have a role in matrix remodeling during ovulation in mice, which involves dissolution of connective matrix and cellular layers. A. ADAMTS-1-deficient mice displayed impaired ovulation, and the authors proposed that this was at least partially caused by...

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Antioxidant protein 2 (AOP2) is a member of a family of thiol‐specific antioxidants, recently renamed peroxiredoxins, that evolved as part of an elaborate system to counteract and control detrimental effects of oxygen radicals. AOP2 is found in endothelial cells, erythrocytes, monocytes, T and B cells, but not in granulocytes. AOP2 was found solely in the cytoplasm and was not associated with the nuclear or membrane fractions; neither was it detectable in plasma. Further experiments focused on the function of AOP2 in erythrocytes where it is closely associated with the hemoglobin complex, particularly with the heme. An investigation of the mechanism of this interaction demonstrated that the conserved cysteine‐47 in AOP2 seems to play a role in AOP2‐heme interactions. Recombinant AOP2 prevented induced as well as noninduced methemoglobin formation in erythrocyte hemolysates, indicating its antioxidant properties. We conclude that AOP2 is part of a sophisticated system developed to protect and support erythrocytes in their many physiological functions.

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