Stimulation of collagen biosynthesis by flavonoid glycosides in skin fibroblasts of osteogenesis imperfecta type I and the potential mechanism of their action

Abstract

Abstract. The aim of the present study was to identify bioactive compounds stimulating collagen biosynthesis with potential for osteogenesis imperfecta (OI) type I pharmacological therapy. Of the compounds tested, apigenin glycosides 7-O-glucuronide, 7-O-methylglucuronide and pectolinarin at 30 μM were found to significantly induce collagen type I synthesis in OI fibroblasts without an effect on the overall protein synthesis. None of the compounds displayed any toxicity at that concentration. Secretion of collagen into media was not affected by apigenin 7-Oglucuronide and was slightly increased in cells treated with apigenin 7-O-methylglucuronide and pectolinarin. Furthermore, procollagen secreted by treated cells underwent a more rapid processing into collagen as compared with control untreated cells. In addition, we elucidated the possible mechanism involved in their action. Stimulation of collagen biosynthesis was not due to an increase in cell proliferation, because no differences in DNA content between the compound-treated and untreated cells were observed. Since flavonoids are known as strong inhibitors of metalloproteinases degrading matrix proteins, the increased level of collagen could result from the inhibition of their activity. However, the compounds with a stimulatory effect on collagen synthesis did not influence the activities of collagenase type I, gelatinases A and B, and stromelysin. On the contrary, all compounds stimulated the activity of prolidase which catalyzes the final step of collagen degradation and plays an important role in collagen biosynthesis. Stimulation of collagen synthesis and prolidase activity by apigenin 7-Oglucuronide was accompanied by an increase in IGF-I receptor expression. In contrast, the compounds apigenin 7-O-methylglucuronide and pectolinarin which normalized collagen synthesis in OI cells may exert their effects through ß1-integrin-mediated signaling.

Differential effect of flavonoids on glycosaminoglycan content and distribution in skin fibroblasts of patients with type I osteogenesis imperfecta

“…2A). Similarly, a different effect on GAG content was observed in contrast to the essential stimulatory activity of the apigenin glycosides [5] and [6] and pectolinarin [9] in collagen biosynthesis (10). The increase in sulphated GaG content in the presence of apigenin 7-O-glucuronide [5] was approximately 2 times lower than that observed in the presence of apigenin [1].…”

“…However, pectolinarin [9] caused a decrease in GAG content of ~40%. Of the other tested flavonoids, isokaempferide 7-O-glucoside [10] showed a similar effect to pectolinarin [9], decreasing GAG content by ~30% (Fig. 2A).…”

“…Treatment of OI cells with the aglycones apigenin [1] and quercetin [4], which inhibited both collagen and non-collagen protein biosynthesis (10), caused the greatest increase in GAG concentration ( Fig. 2A).…”

“…In the fibroblasts of patients with a mild form of OI type I and a detected 'null allele' in the COL1A1 gene (21), an approximate 1.5-fold increase in GAG concentration in medium was observed. Previously, we studied the effect of various flavonoids on collagen biosynthesis in OI fibroblasts (10). Among these, the apigenin glycosides 7-O-glucuronide, 7-O-methylglucuronide and pectolinarin specifically affected collagen biosynthesis without influencing the overall protein biosynthesis.…”

“…Previously, we demonstrated that disturbances of collagen type I biosynthesis in the skin fibroblasts of patients with OI type I were normalized by treatment of the cells with certain flavonoid glycosides (10). Flavonoids, which are plant polyphenolic compounds, are known to have a number of biological activities, including anti-oxidant, anti-radical, anti-flammatory, anti-microbial, anti-allergy and anti-apoptic effects (11)(12)(13).…”