Artificial Extracellular Matrices with Oversulfated Glycosaminoglycan Derivatives Promote the Differentiation of Osteoblast-Precursor Cells and Premature Osteoblasts

Abstract

Sulfated glycosaminoglycans (GAG) are components of the bone marrow stem cell niche and to a minor extent of mature bone tissue with important functions in regulating stem cell lineage commitment and differentiation. We anticipated that artificial extracellular matrices (aECM) composed of collagen I and synthetically oversulfated GAG derivatives affect preferentially the differentiation of osteoblast-precursor cells and early osteoblasts. A set of gradually sulfated chondroitin sulfate and hyaluronan derivatives was used for the preparation of aECM. All these matrices were analysed with human bone marrow stromal cells to identify the most potent aECM and to determine the influence of the degree and position of sulfate groups and the kind of disaccharide units on the osteogenic differentiation. Oversulfated GAG derivatives with a sulfate group at the C-6 position of the N-acetylglycosamine revealed the most pronounced proosteogenic effect as determined by tissue nonspecific alkaline phosphatase activity and calcium deposition. A subset of the aECM was further analysed with different primary osteoblasts and cell lines reflecting different maturation stages to test whether the effect of sulfated GAG derivatives depends on the maturation status of the cells. It was shown that the proosteogenic effect of aECM was most prominent in early osteoblasts.

The role of pleiotrophin in bone repair

“…The first category comprised the articles concerning the in vitro or in vivo expression of PTN [6,[8][9][10][11][12][13][14][15] or its receptors [8,9,[16][17][18][19][20] in cells of the bone or the cartilage tissue. The second category included the studies, which examined actions and possible mechanisms of PTN [8,[21][22][23][24][25][26][27] or its receptors [8,16,17,[28][29][30][31] actions in bone cells. The third category comprised of the studies, which investigate the macroscopic effects of altered PTN expression on bone formation and/or remodelling in animal models [8,[32][33][34][35][36][37][38][39][40] or in clinical studies [41].…”

“…Artificial extracellular matrices composed of collagen I and synthetically over-sulfated GAGs reveal significant proosteogenic effect, as determined by tissue nonspecific alkaline phosphatase activity and calcium deposition, especially when tested in early osteoblasts [31]. An increase of total sulfated GAGs was observed 4 weeks after supraspinatus tendon overuse, which remained elevated up to 16 weeks [20].…”

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

“…Indeed, it has been shown that synthetically sulfated GAG derivatives promote osteogenic differentiation of human mesenchymal stromal cells and influence manifold cellular functions (14,25,27). Additionally, sulfated GAGs were shown to inhibit the bone degradation by osteoclasts (72) and to provide immunomodulation properties (73).…”

“…The use of sulfated GAGs could be a promising approach in bone grafting because in vitro studies showed promoting effects on osteogenesis (3,14). However, besides stimulating bone formation and reducing bone resorption, the alteration of GAG concentrations has also been reported to correlate with cancer progression by activating oncogenic pathways (92), promoting invasion and metastasis (93), and accelerating shedding of extracellular vesicles (94,95), which have to be carefully evaluated prior to clinical application.…”

“…Moreover, they interact with and modulate the function of proteins like cytokines, adhesion molecules, and enzymes and thereby regulate processes such as migration, adhesion, differentiation, and proliferation of bone cells (2, 4 -13). Thus, because human bone marrow stromal cells (hBMSC) sense their microenvironment, especially the chemical composition of the ECM (14), GAGs also promote the differentiation of bone-forming osteoblasts from hBMSC, as different studies have shown for sulfated GAGs (15,16). Additionally, GAGs are potent molecules to promote bone anabolic activities (2).…”