Mitogenic activity of hydroxyapatite: Requirement for somatomedin C

Abstract

Synovial hyperplasia is a feature of the chronic synovitis associated with basic calcium phosphate crystals [hydroxyapatite (HA), octacalcium phosphate, tricalcium phosphate] and calcium pyrophosphate. Each of these crystals stimulated mitosis of cultured human skin fibroblasts or canine synovial fibroblasts in a concentration-dependent fashion. We examined the effect of pure somatomedin C (Sm-C) on HA crystal induced mitogenesis. Confluent cultures of human fibroblasts were rendered quiescent by incubation in the presence of 1% platelet-poor-Sm-C free plasma (PPSCFP) for 24 hours. HA crystals stimulated thymidine incorporation 2.3-fold over control value. Addition of Sm-C significantly augmented the effect of HA crystals (P less than 0.01). Nearly identical effects were observed in the presence of 100 micrograms/ml HA crystals or 15 ng/ml PDGF. Monoclonal antibodies against Sm-C had little effect on the basal 3H thymidine uptake by control cells incubated in 1% PPSCFP but blocked over 50% of the HA crystal or PDGF-induced 3H thymidine incorporation both in the presence or absence of Sm-C. The incomplete blocking suggested either the presence of other "progression" factors, such as insulin-like growth factor II in the conditioned media or the possibility that HA or PDGF in high enough dosage enabled cells to escape their dependence on Sm-C for DNA synthesis.

Induction of Early Growth Response Gene Egr2 by Basic Calcium Phosphate Crystals through a Calcium-Dependent Protein Kinase C-Independent p44/42 Mitogen-Activated Protein Kinase Pathway

“…It has been reported that BCP crystals can act like growth factor PDFG to exert a number of Ca 2+ -dependent early cell cycle events [Cheung et al, 1986]. Mazer et al [1991] demonstrated that induction of Egr2 gene expression is a Ca 2+ -dependent process.…”

Molecular Mechanism of the Induction of Metalloproteinases 1 and 3 in Human Fibroblasts by Basic Calcium Phosphate Crystals

“…At concentrations found in pathologic human joint fluids, these crystals exert biological effects on cultured cells in a manner similar to growth factors like platelet-derived growth factor, epidermal growth factor, and serum. It has been demonstrated that BCP crystals stimulate fibroblast, synoviocyte, and chondrocyte mitogenesis in vitro (3); stimulate the production of prostaglandin via the phospholipase A 2 /cyclo-oxygenase pathway (4); activate phospholipase C and inositol phospholipid hydrolysis (5); induce the expression of the proto-oncogenes, c-fos and c-myc (6,7); and induce the synthesis and secretion of metalloproteinases (MMPs) 1, 3, 8, and 13 (8 -12). In contrast to other mitogenic and growth factors, BCP crystal-elicited signal transduction pathways have not been completely studied.…”

The role of crystals in articular tissue degeneration

“…Stimulation of fibroblasts or chondrocytes results in activation of phospholipase C and inositol phospholipid hydrolysis [12,13], expression o proto-oncogenes [c-fos and c-myc] [14,17], induction of metalloproteinases (MMP-1, -3, and -9) [11,16,17] and mitogenesis [18,19].…”