Bioactive effects of silica nanoparticles on bone cells are size, surface, and composition dependent.

Silica based nanoparticles have been demonstrated to have intrinsic biologic activity towards the skeleton and to function by promoting the differentiation of bone forming osteoblasts while inhibiting the differentiation of bone resorbing osteoclasts. The excitement surrounding nanomedicine in part revolves around the almost unlimited possibilities for varying the physicochemical properties including size, composition, and surface charge. To date few studies have attempted to manipulate these characteristics in concert to optimize a complex biologic outcome. Towards this end, spherical silica nanoparticles of various sizes (50-450 nm), of different surface properties (OH, CO2H, NR4+, mNH2), and of different composition (silica, gold, and polystyrene) were synthesized and evaluated for biological activity toward skeletal cells. Osteoblast activity was most influenced by composition and size variables, whereas osteoclasts were most affected by surface property variation. The study also establishes nanoparticle mediated suppression of Nfatc1, a key transcriptional regulator for osteoclast differentiation, identifying a novel mechanism of action. Collectively, the study highlights how during the design of bioactive nanoparticles, it is vital to consider not only the myriad of physical properties that can be manipulated, but also that the characteristics of the target cell plays an equally integral role in determining biological outcome. STATEMENT OF SIGNIFICANCE: Silica nanomaterials represent a promising biomaterial for beneficial effects on bone mass and quality as well as regenerative tissue engineering and are currently being investigated for intrinsic bioactivity towards the primary cells responsible for skeletal homeostasis; osteoblasts and osteoclasts. The goal of the current study was to assess the physical properties of silica nanoparticles that impart intrinsic bioactivity by evaluating size, surface charge, and composition. Results reveal differential influences of the physical properties of nanoparticles towards osteoblasts and osteoclasts. This study provides new insights into the design of nanoparticles to specifically target different aspects of bone metabolism and highlights the opportunities provided by nanotechnology to modulate a range of cell specific biological responses for therapeutic benefit.

CTLA-4Ig (abatacept) balances bone anabolic effects of T cells and Wnt-10b with antianabolic effects of osteoblastic sclerostin.

Activated lymphocytes promote inflammation and bone destruction in rheumatoid arthritis (RA), making T cells and B cells therapeutic targets. Indeed, pharmacological blockade of CD28 costimulation using CTLA-4Ig (abatacept), approved for amelioration of RA, renders T cells dormant (anergic). CTLA-4Ig also promotes bone accretion in healthy mice; surprisingly, however, this effect is driven exclusively through upregulation of bone formation, rather than anti-inflammatory effects on resorption. In the study presented here, we utilized T cell receptor ß gene and Wnt-10b gene knockout mice to investigate the roles of T cells and Wnt-10b in CTLA-4Ig-induced bone anabolism. Ablation of either T cells or Wnt-10b not only abolished CTLA-4Ig-induced bone anabolism but also, paradoxically, suppressed bone formation leading to bone loss. Stalled bone formation was accompanied by bone marrow stromal cell expression of the Wnt pathway inhibitor sclerostin. Our data suggest that an immunoskeletal pivot may promote or suppress bone formation, depending on the net outcome of CTLA-4Ig action directed independently on T cells and osteoblast-linage cells that counter Wnt-10b-induced bone anabolism, by secretion of sclerostin. While CTLA-4Ig action is tipped in favor of bone formation under physiological conditions, pathological immunodeficiency may lead to suppressed bone formation and skeletal damage.

Nano-Hydroxyapatite Stimulation of Gene Expression Requires Fgf Receptor, Phosphate Transporter, and Erk1/2 Signaling.

Hydroxyapatite (HAp) is critical to health both as the main structural material of the skeleton and storage material of calcium and phosphate. Nanosized HAp (nHAp) is naturally produced by mineralizing cells during bone formation and remodeling and is the main constituent of the skeleton. As such, HAp is currently being investigated as a therapeutic biomaterial for orthopedic and dental purposes. Recent studies have suggested that extracellular nHAp can influence osteoblast lineage commitment and cell function through changes in gene expression; however, the mechanisms remain to be elucidated. Here, the cellular and molecular mechanism by which rod-shaped nHAp (10 × 100 nm) stimulates gene expression in preosteoblast bone marrow stromal cells was investigated. Electron microscopy detected a rapid and stable interaction of nHAp with the cell membrane, which correlated with a strong stimulation of the Erk1/2 signaling pathway. Results also identified the requirement of the Fgf receptor signaling and phosphate-transporters for nHAp regulated gene expression whereas a calcium-sensing receptor inhibitor had no effect. Collectively, the study uncovers novel signaling pathways and cellular events specifically stimulated by and required for the cellular response to free extracellular HAp. The results provide insight into the osteoblastic response to HAp relevant to functional mineralization and pathological calcification and could be used in the development of biomaterials for orthopedic purposes.