Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with very different polysaccharide binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal β-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signaling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than expected. These super-bioactive nanostructures may enable many therapies in the horizon involving proteins.

This animal study presents data suggesting that the use of intra-articular vancomycin powder for reducing the risk of periprosthetic joint infections should be investigated further in clinical studies.

3.

While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.