Saggio, Isabella

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Isabella saggio

Archivio della ricerca- Università di Roma La Sapienza

Perils and Promises of Therapeutic Approaches forthe Stem Cell Disease Fibrous DysplasiaISABELLA SAGGIOIn the paper “HDAC8, a Potential TherapeuticTarget, Regulates Proliferation and Differentia-tion of Bone Marrow Stromal Cells in FibrousDysplasia” [1], the authors fuse three elementsof interest. First, and central, is the diseaseaddressed: fibrous dysplasia (FD), a raregenetic condition associated with human bonemarrow stromal cells (BMSCs), a population ofadult stem cells whose specific biology andtranslational potential make the second ele-ment of interest in the story. Third, is the epi-genetic component: the indication of histonedeacetylase 8 (HDCA8), a zinc-dependent HDACsubtype, as potential therapeutic target for FD.FD (OMIM#174800) is a rare postnatal dis-ease linked to somatic mutations in the GNASlocus, modifying the encoded Gs-α product atresidue 201, prevalently with R201C or R201Hamino acidic substitutions [2]. These mutationsconvert the α subunit of the stimulatory G pro-tein into a constitutively active engine, leadingcells to overproduce cAMP, a central player incell metabolism. Although the biochemistry ofGs-α mutations was dissected more than15 years ago [3, 4], FD molecular pathophysiol-ogy is not yet fully defined. However, histologi-cal features of FD tissues are well-known,including bone with abnormal trabecular pat-tern, osteomalacia, enhanced resorption, andmarrow fibrosis, which results from accumula-tion of osteogenic precursors, loss of adipocytesand hematopoiesis, and altered vascularity [2].The contribution of bone marrow to thepathological process points to FD as a disease ofthe bone/bone marrow organ, in which contextBMSCs play a pivotal role. Key experimental evi-dence of this principle came from the analysis ofectopic ossicles generated in mice implantedwith FD patients’ BMSCs or exogenously engi-neered, GNASR201C expressing, BMSCs [5, 6]. Inboth cases, it was demonstrated how bone andbone marrow alterations were detectable in thechimeric human/mouse organs generatedin vivo. These data imply that the use of BMSCsis determinant for understanding FD, and fordesigning and testing innovative therapeuticstrategies, but also suggest that FD studies arehelpful for dissecting the role played by thisadult stem cell population in the physiology ofbone/bone marrow relationships. This conceptmakes FD one—among many—paradigmaticexample underlying how science is synergic andinterrelated in the advancement of knowledge,beyond boundaries established between appliedand basic research.Current FD therapies are not yet cures. FDpatients, whose clinical symptoms can be highlyinvalidating, are treated with surgical interven-tions and with drugs controlling bone metabo-lism, such as bisphosphonates, derivatives ofinorganic pyrophosphate, largely used for oste-oporotic conditions. In the more recent years,antibodies have been investigated for treatingFD. This approach has created new hopes, alsobased on the high success rate of immunother-apies for other diseases. A candidate route forFD therapy is based on the use of anti-RANKLhumanized antibodies, as the Food and DrugAdministration (FDA) approved Denosumab.RANKL is a key mediator in the response ofbone cells to osteoclast precursors, is highlyexpressed in FD patient samples and in BMSCsexpressing the GNASR201C mutation, whichsuggests a molecular explanation for excessiveFD bone resorption along with pointing to thismolecule as druggable target [5]. Other molecu-lar approaches are also being investigated,albeit directed toward more generalized effectsobserved in FD, as the inhibitor of IL-6, Tocilizu-mab, which targets a disease-induced inflam-matory condition paralleling strategies appliedto rheumatoid arthritis.Xiao et al. suggest another route for inter-vention on FD, based on the exploitation ofepigenetic manipulation of cell metabolism viaHDAC8 inhibitors [1]. HDACs control globalchromatin organization and gene expression,contributing to multiple biological pathwaysand affecting numerous disease conditionsincluding cancer, autoimmune diseases andneurodegenerative conditions. HDACs haverobustly entered into the panoply of diseasetreatments. Clinicaltrials.com lists 653 studiesbased on histone deacetylases, mainly addres-sing cancer, but also targeting bone conditions.HDCA8 is a zinc-dependent class I, ubiquitouslyDepartment of Biology andBiotechnology, SapienzaUniversity, Rome, Italy andNanyang TechnologicalUniversity, SingaporeCorrespondence: Isabella Saggio,PhD, Department of Biology andBiotechnology, Sapienza University,Piazzale Aldo Moro 5, 00185 Rome,Italy. Telephone: 390649912870;e-mail: isabella.saggio@uniroma1.itReceived September 30, 2018;accepted for publication October22, 2018.http://dx.doi.org/10.1002/sctm.18-0213This is an open access articleunder the terms of the CreativeCommons Attribution-NonCommercial-NoDerivsLicense, which permits use anddistribution in any medium, pro-vided the original work is prop-erly cited, the use is non-commercial and no modificationsor adaptations are made.STEM CELLS TRANSLATIONAL MEDICINE 2018;00:1–2 www.StemCellsTM.com © 2018 The AuthorsSTEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed PressCOMMENTARYexpressed deacetylase, which affects multiple substrates andregulates diverse physiological and pathological processes [7].Importantly for the FD setting, HDAC8 impinges on BMSCsosteogenic differentiation. Xiao et al. show that HDAC8 inhibi-tion alters FD disease properties, by acting on the cAMPrelated cell phenotype and promoting osteogenesis in vivo [1].Beyond this study, the implementation of epigenetic therapiesfor FD has solid bases in the fact that the differentiation prop-erties and the related epigenetic status of FD BMSCs are pro-foundly implicated in the disease, since FD mutations, byinducing overproduction of cAMP, directly impact on cAMPresponsive elements (CRE) and related transcription control byCRE binding proteins [8].As outlined above, current strategies for FD include multi-ple treatments to control or rescue mutation consequences,including the use of bone metabolism affecting drugs, andapproaches targeting single molecular interactions as in thecase of anti-RANKL antibodies, or multiple molecular events aswith HDAC8 inhibitors. However, the overview of current FDtherapeutic options would not be complete if not integratedwith the concept of tissue engineering approaches based onBMSCs. Genetic or metabolic correction of autologous FDBMSCs along with heterologous wild-type bone progenitorscan be used to create bone grafts with potential dominantpositive effects on clinical FD phenotypes. To this goal ex vivoor in vivo genetic manipulation of BMSCs is particularly rele-vant. Xiao et al. demonstrate that they can use vectors toinhibit HDAC8 overproduction observed in FD cells by expres-sing RNA interfering encoded sequences [1]. We used RNAinterference to correct FD BMSCs identifying allele specificsequences targeting the GNASR01C mutation [5]. Furthermore,evolution of these concepts will be the use in FD of CrisprCasgenome editing for in situ disease mutation correction [9].If therapies for human diseases have always to be evalu-ated as a success versus risk ratio, there are some importantcaveat linked to the specific elements highlighted above. Theseinclude off targets effect of epigenetic manipulation. HDACsaffect the epigenome at large impinging in unpredictable wayson the overall organismal biology. However, highly targeted,disease correction frontier tools require precaution too. Crispr-Cas technology, for example, is dealing with undesired editingand off target mutations [9]. Lastly, but certainly not least,perils in tissue engineering strategies involving BMSCs are alsoto be taken into account. Although the regeneration potentialof adult stem cell is robustly assessed, the specific nature ofcells possessing this potential, purification protocols, tissuesinto which cells can differentiate, are elements complexity [10].Latest data show that there is a fine developmental hierarchyin adult stem cell progenitors generating bone, with the mostup to date phenotype identifiable via differential expression ofPDPN, CD146, CD73, and CD164 markers [11]. Usage of BMSCsfor clinical application (or of mesenchymal stem cells) requiresstrict purification protocols and full marker phenotyping. Alongwith this, such experimental therapeutic strategies need sys-tematic assessment of efficacy and safety in preclinical settings,as human ossicles described by Xiao et al., but also animalmodels, now available for FD [12, 13].DISCLOSURE OF POTENTIAL CONFLICTS OF INTERESTThe author indicated no potential conflicts of interest.REFERENCES1 Xiao T, Fu Y, Zhu W et al. HDAC8, apotential therapeutic target, regulates prolif-eration and differentiation of bone marrowstromal cells in fibrous dysplasia. STEM CELLSTRANSLATIONAL MEDICINE 2018; in press.2 Bianco P, Wientroub S, Dysplasia F.Fibrous dysplasia. In: Glorieux FH, Pettifor JM,Juppner H, eds. Pediatric Bone: Biology andDisease. 2nd ed. New York, NY: Elsevier, 2012:589-624.3 Landis CA, Masters SB, Spada A et al.GTPase inhibiting mutations activate thealpha chain of Gs and stimulate adenylylcyclase in human pituitary tumours. Nature1989;340:692-696.4 Bourne HR, Landis CA, Masters SB.Hydrolysis of GTP by the alpha-chain of Gsand other GTP binding proteins. Proteins1989;6:222-230.5 Piersanti S, Remoli C, Saggio Iet al. Transfer, analysis, and reversion of thefibrous dysplasia cellular phenotype in humanskeletal progenitors. J Bone Miner Res 2010;25:1103-1116.6 Riminucci M, Saggio I, Robey PGet al. Fibrous dysplasia as a stem celldisease. J Bone Miner Res 2006;21:P125-P131.7 Chakrabarti A, O’ehme I, Witt Oet al. HDAC8: A multifaceted target for thera-peutic interventions. Trends Pharmacol Sci2015;36:481-492.8 Mayr B, Montminy M. Transcriptionalregulation by the phosphorylation-dependentfactor CREB. Nat Rev Mol Cell Biol 2001;2:599-609.9 Knott GJ, Jennifer AD. CRISPR-Casguides the future of genetic engineering.Science 2018;361:866-869.10 Sipp D, Robey P, Turner L. Clear up thisstem-cell mess. Nature 2018;561:455-457.11 Chan CKF, Gulati GS, Sinha RTet al. Identification of the human skeletalstem cell. Cell 2018;175:43-56.12 Saggio I, Remoli C, Spica E et al. Con-stitutive expression of Gsalpha(R201C) inmice produces a heritable, direct replica ofhuman fibrous dysplasia bone pathology anddemonstrates its natural history. J BoneMiner Res 2014;29:2357-2368.13 Khan SK, Yadav PS, Elliott Get al. Induced Gnas(R201H) expression from theendogenous Gnas locus causes fibrous dysplasiaby up-regulating Wnt/beta-catenin signaling.Proc Natl Acad Sci USA 2018;115:E418-E427.© 2018 The Authors STEM CELLS TRANSLATIONAL MEDICINE published byWiley Periodicals, Inc. on behalf of AlphaMed PressSTEM CELLS TRANSLATIONAL MEDICINE2 Therapy for Fibrous Dysplasia

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

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

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