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Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein α 2 -Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D-rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.

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We present data suggesting a function of ␣ 2 -HS glycoproteins/fetuins in serum and in mineralization, namely interference with calcium salt precipitation. Fetuins occur in high serum concentration during fetal life. They accumulate in bones and teeth as a major fraction of noncollagenous bone proteins. The expression pattern in fetal mice confirms that fetuin is predominantly made in the liver and is accumulated in the mineralized matrix of bones. We arrived at a hypothesis on the molecular basis of fetuin function in bones using primary rat calvaria osteoblast cultures and salt precipitation assays. Our results indicate that fetuins inhibit apatite formation both in cell culture and in the test tube. This inhibitory effect is mediated by acidic amino acids clustering in cystatin-like domain D1. Fetuins account for roughly half of the capacity of serum to inhibit salt precipitation. We propose that fetuins inhibit phase separation in serum and modulate apatite formation during mineralization.

Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation and death pathway selection in systemic lupus erythematosus. Treatment with rapamycin, which effectively controls disease activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, suggesting that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. In this article, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells. S ystemic lupus erythematosus (SLE)3 is an autoimmune disease of unknown etiology characterized by T and B cell dysfunction and production of antinuclear Abs (1). Dysregulation of cell death is thought to play a key role in driving antinuclear Ab production, since the source of immunogenic nuclear material is necrotic or apoptotic cells in SLE (2). There is enhanced spontaneous apoptosis of circulating T cells in SLE, which has been linked to chronic lymphopenia (3) and compartmentalized release of autoantigens (4). Paradoxically, there is decreased activation-induced T cell death in SLE (5-7), which may contribute to persistence of autoreactive cells.The mitochondria play crucial roles in activation and death pathway selection in T lymphocytes (2). Lupus T cells exhibit mitochondrial dysfunction, which is characterized by the elevation of the mitochondrial transmembrane potential (⌬ m ) or persistent mitochondrial hyperpolarization (MHP) and consequential ATP depletion, resulting in decrease of activation-induced apoptosis and predisposition of T cells for necrosis (6). ATP depletion in lupus T cells was recently confirmed by Krishnan et al. (8). We proposed that increased release of necrotic materials from T cells could drive disease pathogenesis by activating macrophages and dendritic cells and enhancing their capacity to produce NO and IFN-␣ in SLE (2). Indeed, dendritic cells exposed to necrotic, but not apoptotic, cells induce lupus like-disease in MRL mice and accelerate the disease of MRL/lpr mice (9).Enhanced T cell activation-induced calcium fluxing has been identified as a central defect in abnormal activation and cytokine production by lupus T cells (10). Induction of MHP and mitochondrial biogenesis by NO augments cytoplasmic calcium levels and regenerates the enhanced rapid calcium signaling profile of lupus T cells (11). Dysregulation of signaling through the TCR has also been shown to be a critical determinant of abnormal calcium fluxing in SLE (12, 13). The TCR/CD3 -chain (TCR) expression is diminished in SLE T cells, and it is functionally replaced by the FcR type I ␥-chain (FcRI␥), a protein normally found in other cell types (14). TCR signaling through FcRI␥ and its adaptor protein Syk is associated with elevated calcium fluxing but only in the absence of TCR (12). It has been shown that forced expression of The costs of publication of this article were defrayed in part by the payment of page charges. This ...