Intracellular calcium responses to basic calcium phosphate crystals in fibroblasts

Abstract

The initial transient [Ca2+]i increase probably serves as a second messenger leading to activation of early cellular responses such as c-fos expression which is important in BCP crystal-induced mitogenesis. The second, slower and more sustained rise of [Ca2+]i probably initiates other cellular processes needed for fibroblast mitogenesis.

Fetuin-A Regulation of Calcified Matrix Metabolism

“…57 Calcium phosphate crystals induce proinflammatory cytokine secretion through the NLRP3 inflammasome in monocytes/macrophages, 58 -60 cell death in human vascular smooth muscle cells, 61 and cell activation in chondrocytes. [62][63][64] Antiapoptotic activity of fetuin-A has been observed in smooth muscle cells 65 and dampening of the cell-specific responses would generally be expected to alleviate the detrimental consequences of local inflammation, cell death, and cartilage degradation. The proven protective function of fetuin-A in many animal models of inflammation, 52-55 the inhibition of proinflammatory compounds, 50,51,66 -68 and the inhibition of crystalinduced neutrophil activation 57 collectively suggest that fetuin-A may generally protect during pathological mineralization as well.…”

Basic Calcium Phosphate Crystals Induce Monocyte/Macrophage IL-1β Secretion through the NLRP3 Inflammasome In Vitro

“…The other mechanism of crystal activation involves a direct crystal-cell membrane interaction due either to electrostatic bonds with naked crystal surface or through membrane receptor stimulation by naked or protein-coated crystals (10). Thus, BCP crystals activate TNF-a production through TLR-4 (11), and crystal-cell interactions induce rapid calcium influx (12), cytoplasmic membrane permeability modification (13), and chondrocyte apoptosis, which is enhanced by annexin V coating (14). They can induce several cellular functions including human foreskin fibroblast proliferation, proto-oncogene stimulation, inflammatory cytokine (IL1b and TNF-a) and NO production, metalloprotease production and activation, cyclooxygenase-1 and cyclooxygenase-2, and PGE 2 *Department of Rheumatology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland;…”

Basic Calcium Phosphate Crystals Activate p44/42 MAPK Signal Transduction Pathway via Protein Kinase Cμ in Human Fibroblasts

“…The mobilized Ca 2ϩ in the cytosol then modifies the activation of PKC␣ by DAG and induces its translocation to the plasma membrane where it becomes physiologically active (51). Some of the mobilized Ca 2ϩ diffuses through the nuclear pores into the nucleus (52,53) where it enhances the BCP crystal induction of c-fos mRNA (10). PKC␣ can also be redistributed from the cytosol to the nucleus as recently noted in NIH 3T3 fibroblasts (54).…”

“…7 and to the hypothesis that BCP crystal activation of HF follows two independent pathways. One pathway is the calcium-dependent PKC pathway characterized by PKC␣ and modulated by mobilized intracellular Ca 2ϩ generated by the sequential hydrolysis of phospholipase C-phosphatidylinositol 1,4,5-bisphosphatephosphatidylinositol 1,4,5-trisphosphate (48 -50) by transient opening of the Ca 2ϩ channel and by crystal endocytosis and dissolution (10). The mobilized Ca 2ϩ in the cytosol then modifies the activation of PKC␣ by DAG and induces its translocation to the plasma membrane where it becomes physiologically active (51).…”

“…We have demonstrated that BCP crystals stimulate the proliferation and synthesis of matrix metalloproteinases (MMPs) in cultured human foreskin and synovial fibroblasts (5)(6)(7)(8)(9). The addition of BCP crystals to the growth medium yielded an immediate 10-fold rise in the intracellular calcium level and a second rise starting at 60 min and lasting for 3 h. This second rise in the intracellular calcium level is probably because of the intracellular dissolution of phagocytosed crystals, which may activate a variety of calcium-dependent signals and induce sustained cell proliferation and MMP synthesis (10).…”