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Deciphering BMSC Deficits in Fibrous Dysplasia in the Search for New Therapeutic Approaches

Review of “HDAC8, A Potential Therapeutic Target, Regulates Proliferation and Differentiation of Bone Marrow Stromal Cells in Fibrous Dysplasia” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Mutations in the guanine nucleotide‐binding protein alpha‐stimulating activity polypeptide, GNAS, gene lead to the overproduction of cyclic AMP (cAMP) and the onset of fibrous dysplasia (FD), a non‐hereditary and benign bone disease characterized by the high proliferation [1] and inhibited osteogenesis of bone marrow stem cells (BMSCs). These unwanted alterations lead to the replacement of normal healthy bone and marrow by fibrous tissue and immature porous bone [2], leading to bone pain, deformities, and fractures.

Given the current lack of treatment options other than osteoclastic suppressor related‐drugs and surgical intervention to reconstruct lesion sites [3], researchers from the laboratory of Hongbing Jiang (Nanjing Medical University, Jiangsu Province, China) set out to fully decipher the functional deficits of FD-BMSCs in the hope of encountering a potentially druggable target. Reporting in STEM CELLS Translational Medicine, Xiao et al. now demonstrate how targeting the cAMP‐CREB1‐HDAC8 axis in BMSCs may now provide an effective therapeutic approach for fibrous dysplasia patients [4]. 

Previous studies from the group established histone deacetylase 8 (HDAC8) as a transcriptional repressor, functioning by regulating histone H3 lysine 9 acetylation and by interacting with the osteogenesis‐related transcription factor runt‐related transcription factor 2 (RUNX2) during the osteogenesis of BMSCs [5]. These findings hinted at a potential link between HDAC8 and the suppressed osteogenic potential of FD-BMSCs.

Interestingly, the authors discovered that the increased activity of the cAMP‐CREB1 pathway in FD-BMSCs promoted the transcription of HDAC8, and this, in turn, enhanced FD-BMSC proliferation, decreased apoptosis, and impaired osteogenic differentiation due to the inhibition of both TP53 and RUNX2 expression. Furthermore, the study identified HDAC8 as a transcriptional target gene of CREB1 (cAMP Responsive Element Binding Protein 1) in FD-BMSCs. However, cAMP inhibition by bupivacaine reduced HDAC8 expression increased TP53 expression, and led to the partial reversion of the fibrous dysplasia phenotype, while HDAC8 inhibition via PCI‐34051 inhibited the disease-inducing activities of cAMP and enhanced FD-BMSC osteogenesis following implantation into nude mice.

Overall, these data highlight a critical link between HDAC8 and the enhanced proliferation and impaired osteogenic differentiation of BMSCs derived from fibrous dysplasia patients and suggest specific small molecule inhibitors of HDAC8 as an exciting new therapeutic approach for fibrous dysplasia.

For more on the stem cell deficits observed in fibrous dysplasia and possible treatment strategies, stay tuned to the Stem Cells Portal!


  1. Marie PJ, de Pollak C, Chanson P, et al., Increased proliferation of osteoblastic cells expressing the activating Gs alpha mutation in monostotic and polyostotic fibrous dysplasia. American Journal of Pathology 1997;150:1059-69.
  2. Khan SK, Yadav PS, Elliott G, et al., Induced GnasR201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling. Proceedings of the National Academy of Sciences 2018;115:E418-E427.
  3. Faruqi T, Dhawan N, Bahl J, et al., Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders %J BioMed Research International. BioMed Research International 2014;2014:16.
  4. Xiao T, Fu Y, Zhu W, et al., HDAC8, A Potential Therapeutic Target, Regulates Proliferation and Differentiation of Bone Marrow Stromal Cells in Fibrous Dysplasia. STEM CELLS Translational Medicine 2019;8:148-161.
  5. Fu Y, Zhang P, Ge J, et al., Histone deacetylase 8 suppresses osteogenic differentiation of bone marrow stromal cells by inhibiting histone H3K9 acetylation and RUNX2 activity. The International Journal of Biochemistry & Cell Biology 2014;54:68-77.