A Comprehensive Study on Homeostatic Bone and Bone Marrow Mediators

Bone marrow is an extremely complex tissue, whose function is to accommodate the hematopoietic and the bone stem/progenitor cells. In particular, the bone marrow stromal microenvironment consists of several different types of cells, including bone lining osteoblasts, endothelial cells, reticular adventitial cells, neuronal cells and mesenchymal stem cells. Here, this large number of different populations coexist and exchange several signals in order to preserve bone marrow homeostasis. Accordingly, it is necessary to highlight that changes in the bone marrow steady-state may lead to localized and/or systemic diseases. The characteristics and the properties in the bone and bone marrow environment have been well elucidate for a number of factors, while less is known about other molecules, although they play critical functions within these tissues. Among them, the p62 multidomain protein has been associated with the osteoclastogenic processes, but not well-defined information is, so far, present in the literature regarding its function in the fine-tuned processes underling the bone and bone marrow metabolic features. Recently, we demonstrated that p62 regulates osteoblasts differentiation and that p62 deficiency inhibits the bone turnover rate. Consistently, our studies aimed at analyzing the bone marrow features of p62 KO mice. We showed that a significant adipocyte infiltration, particularly evident during the aging. This observation, together with the finding of a decreased osteolineage cell pools, impaired CXCL12/CXCR4 signaling and hemosiderin accumulation, demonstrated that p62 deficiency is able to disrupt bone marrow niche homeostasis overall in aged mice. The other molecule here studied is the soluble cytokine IFN-γ. By means of administration of a plasmid coding for IFN-γ (pINF-γ) both in ovariectomized (osteopenic) and in the sham-operated mice, we demonstrated that pINF-γ injections induced pathologic bone and bone marrow alterations, characterized by cortical and trabecular bone loss, increased proinflammatory cytokine release and impaired mesenchymal stem cells (MSCs) osteoblastogenic differentiation. In addition, the reduction of CXCL12+ cell number and the observation of hypercellular areas in the bone marrow of sham-operated and ovariectomized mice administered with pINF-γ, further suggest that IFN-γ is an important mediator of bone catabolism. During my PhD course we also investigated the therapeutic effects of a new hyaluronic acid-based hydrogel in a mouse model of knee osteoarthritis. Our results demonstrated that hydrogel administration allowed for the controlled and sustained release of hyaluronic acid, prolonging so the exposure of osteoarthritic knees to this biopolymer and promoting cartilage and subchondral bone regeneration. We also proved that hyaluronic acid-bearing hydrogels were able to counteract osteoarthritis by decreasing on the one hand the expression of pro-inflammatory mediators, while on the other hand by inducing MSCs differentiation and maturation into chondroblasts.