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In the article “HDAC8, a Potential Therapeutic Target, Regulates Proliferation and Differentiation of Bone Marrow Stromal Cells in Fibrous Dysplasia” [1], the authors fuse three elements of interest. First, and central, is the disease addressed: fibrous dysplasia (FD), a rare genetic condition associated with human bone marrow stromal cells (BMSCs), a population of adult stem cells whose specific biology and translational potential make the second element of interest in the story. Third, is the epigenetic component: the indication of histone deacetylase 8 (HDCA8), a zinc-dependent HDAC subtype, as potential therapeutic target for FD. FD (OMIM#174800) is a rare postnatal disease linked to somatic mutations in the GNAS locus, modifying the encoded Gs-α product at residue 201, prevalently with R201C or R201H amino acidic substitutions [2]. These mutations convert the α subunit of the stimulatory G protein into a constitutively active engine, leading cells to overproduce cAMP, a central player in cell metabolism. Although the biochemistry of Gs-αmutations was dissectedmore than 15 years ago [3, 4], FD molecular pathophysiology is not yet fully defined. However, histological features of FD tissues are well-known, including bone with abnormal trabecular pattern, osteomalacia, enhanced resorption, and marrow fibrosis, which results from accumulation of osteogenic precursors, loss of adipocytes and hematopoiesis, and altered vascularity [2]. The contribution of bone marrow to the pathological process points to FD as a disease of the bone/bone marrow organ, in which context BMSCs play a pivotal role. Key experimental evidence of this principle came from the analysis of ectopic ossicles generated in mice implanted with FD patients’ BMSCs or exogenously engineered, GNASR201C expressing, BMSCs [5, 6]. In both cases, it was demonstrated how bone and bone marrow alterations were detectable in the chimeric human/mouse organs generated in vivo. These data imply that the use of BMSCs is determinant for understanding FD, and for designing and testing innovative therapeutic strategies, but also suggest that FD studies are helpful for dissecting the role played by this adult stem cell population in the physiology of bone/bone marrow relationships. This concept makes FD one—among many—paradigmatic example underlying how science is synergic and interrelated in the advancement of knowledge, beyond boundaries established between applied and basic research. Current FD therapies are not yet cures. FD patients, whose clinical symptoms can be highly invalidating, are treated with surgical interventions and with drugs controlling bone metabolism, such as bisphosphonates, derivatives of inorganic pyrophosphate, largely used for osteoporotic conditions. In the more recent years, antibodies have been investigated for treating FD. This approach has created new hopes, also based on the high success rate of immunotherapies for other diseases. A candidate route for FD therapy is based on the use of anti-RANKL humanized antibodies, as the Food and Drug Administration (FDA) approved Denosumab. RANKL is a key mediator in the response of bone cells to osteoclast precursors, is highly expressed in FD patient samples and in BMSCs expressing the GNASR201C mutation, which suggests a molecular explanation for excessive FD bone resorption along with pointing to this molecule as druggable target [5]. Other molecular approaches are also being investigated, albeit directed toward more generalized effects observed in FD, as the inhibitor of IL-6, Tocilizumab, which targets a disease-induced inflammatory condition paralleling strategies applied to rheumatoid arthritis. Xiao et al. suggest another route for intervention on FD, based on the exploitation of epigenetic manipulation of cell metabolism via HDAC8 inhibitors [1]. HDACs control global chromatin organization and gene expression, contributing to multiple biological pathways and affecting numerous disease conditions including cancer, autoimmune diseases and neurodegenerative conditions. HDACs have robustly entered into the panoply of disease treatments. Clinicaltrials.com lists 653 studies based on histone deacetylases, mainly addressing cancer, but also targeting bone conditions. HDCA8 is a zinc-dependent class I, ubiquitously expressed Department of Biology and Biotechnology, Sapienza University, Rome, Italy and Nanyang Technological University, Singapore

Perils and Promises of Therapeutic Approaches for the Stem Cell Disease Fibrous Dysplasia