Vasorin as an actor of bone turnover?

Bone diseases are increasing with aging populations and it is important to identify clues to develop innovative treatments. Vasn, which encodes vasorin (Vasn), a transmembrane protein involved in the pathophysiology of several organs, is expressed during the development in intramembranous and endochondral ossification zones. Here, we studied the impact of Vasn deletion on the osteoblast and osteoclast dialog through a cell Coculture model. In addition, we explored the bone phenotype of Vasn KO mice, either constitutive or tamoxifen-inducible, or with an osteoclast-specific deletion. First, we show that both osteoblasts and osteoclasts express Vasn. Second, we report that, in both KO mouse models but not in osteoclast-targeted KO mice, Vasn deficiency was associated with an osteopenic bone phenotype, due to an imbalance in favor of osteoclastic resorption. Finally, through the Coculture experiments, we identify a dysregulation of the Wnt/ß-catenin pathway together with an increase in RANKL release by osteoblasts, which led to an enhanced osteoclast activity. This study unravels a direct role of Vasn in bone turnover, introducing a new biomarker or potential therapeutic target for bone pathologies.

Sclerostin Antibody-Loaded Dense Collagen Hydrogels Promote Critical-Size Bone Defect Repair.

The management of extensive bone loss remains a clinical challenge. Numerous studies are underway to develop a combination of biomaterials, biomolecules, and stem cells to address this challenge. In particular, the systemic administration of antibodies against sclerostin, a regulator of bone formation, was recently shown to enhance the bone repair efficiency of dense collagen hydrogels (DCHs) hosting murine dental pulp stem cells (mDPSCs). The aim of the present study was to assess whether these antibodies, encapsulated and released from DCHs, could promote craniofacial bone repair by the local inhibition of sclerostin. In vitro studies showed that antibody loading modified neither the hydrogel structure nor the viability of seeded mDPSCs. When implanted in a mouse calvaria critical-size bone defect, antibody-loaded DCHs showed repair capabilities similar to those of acellular unloaded DCHs combined with antibody injections. Importantly, the addition of mDPSCs provided no further benefit. Altogether, the local delivery of antisclerostin antibodies from acellular dense collagen scaffolds is highly effective for bone repair. The drastic reduction in the required amount of antibody compared to systemic injection should reduce the cost of the procedure, making the strategy proposed here a promising therapeutic approach for large bone defect repair.

Role of Physico-Chemical and Cellular Conditions on the Bone Repair Potential of Plastically Compressed Collagen Hydrogels.

Since their first description nearly 20 years ago, dense collagen hydrogels obtained by plastic compression have become popular scaffolds in tissue engineering. In particular, when seeded with dental pulp stem cells, they have demonstrated a great in vivo potential in cranial bone repair. Here, we investigated how physico-chemical and cell-seeding conditions could influence the formation and in vitro mineralization of these cellularized scaffolds. A qualitative assessment demonstrated that the gel stability before and after compression was highly sensitive to the conditions of fibrillogenesis, especially initial acid acetic and buffer concentrations. Gels with similar rheological properties but different fibrillar structures that exhibited different stabilities when used for the 3D culture of Stem cells from Human Exfoliated Deciduous teeth (SHEDs) could be prepared. Finally, in our optimal physico-chemical conditions, mineralization could be achieved only using human dental pulp stem cells (hDPSCs) at a high cell density. These results highlight the key role of fibrillogenic conditions and cell type/density on the bone repair potential of cell-laden plastically compressed collagen hydrogels.

NLRP3 Is Involved in Neutrophil Mobilization in Experimental Periodontitis.

The NLRP3 inflammasome is overexpressed in gingiva of periodontitis patients but its role remains unclear. In our study, we use a periodontitis mouse model of ligature, impregnated or not with Porphyromonas gingivalis, in WT or NLRP3 KO mice. After 28 days of induction, ligature alone provoked exacerbated periodontal destruction in KO mice, compared to WT mice, with an increase in activated osteoclasts. No difference was observed at 14 days, suggesting that NLRP3 is involved in regulatory pathways that limit periodontitis. In contrast, in the presence of P. gingivalis, this protective effect of NLRP3 was not observed. Overexpression of NLRP3 in connective tissue of WT mice increased the local production of mature IL-1ß, together with a dramatic mobilization of neutrophils, bipartitely distributed between the site of periodontitis induction and the alveolar bone crest. P. gingivalis enhanced the targeting of NLRP3-positive neutrophils to the alveolar bone crest, suggesting a role for this subpopulation in bone loss. Conversely, in NLRP3 KO mice, mature IL-1ß expression was lower and almost no neutrophils were mobilized. Our study sheds new light on the role of NLRP3 in periodontitis by highlighting the ambiguous role of neutrophils, and P. gingivalis which affects NLRP3 functions.

Combining sclerostin neutralization with tissue engineering: An improved strategy for craniofacial bone repair.

Scaffolds associated with different types of mesenchymal stromal stem cells (MSC) are extensively studied for the development of novel therapies for large bone defects. Moreover, monoclonal antibodies have been recently introduced for the treatment of cancer-associated bone loss and other skeletal pathologies. In particular, antibodies against sclerostin, a key player in bone remodeling regulation, have demonstrated a real benefit for treating osteoporosis but their contribution to bone tissue-engineering remains uncharted. Here, we show that combining implantation of dense collagen hydrogels hosting wild-type (WT) murine dental pulp stem cells (mDPSC) with weekly systemic injections of a sclerostin antibody (Scl-Ab) leads to increased bone regeneration within critical size calvarial defects performed in WT mice. Furthermore, we show that bone formation is equivalent in calvarial defects in WT mice implanted with Sost knock-out (KO) mDPSC and in Sost KO mice, suggesting that the implantation of sclerostin-deficient MSC similarly promotes new bone formation than complete sclerostin deficiency. Altogether, our data demonstrate that an antibody-based therapy can potentialize tissue-engineering strategies for large craniofacial bone defects and urges the need to conduct research for antibody-enabled local inhibition of sclerostin. STATEMENT OF SIGNIFICANCE: The use of monoclonal antibodies is nowadays broadly spread for the treatment of several conditions including skeletal bone diseases. However, their use to potentialize tissue engineering constructs for bone repair remains unmet. Here, we demonstrate that the neutralization of sclerostin, through either a systemic inhibition by a monoclonal antibody or the implantation of sclerostin-deficient mesenchymal stromal stem cells (MSC) directly within the defect, improves the outcome of a tissue engineering approach, combining dense collagen hydrogels and MSC derived from the dental pulp, for the treatment of large craniofacial bone defects.