PTHrP Modulates the Proliferation and Osteogenic Differentiation of Craniofacial Fibrous Dysplasia-Derived BMSCs

Abstract

Fibrous dysplasia (FD) is a skeletal stem cell disease caused by mutations in the guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene, which results in the abnormal accumulation of cyclic adenosine monophosphate (cAMP) and hyperactivation of downstream signaling pathways. Parathyroid hormone-related protein (PTHrP) is secreted by the osteoblast lineage and is involved in various physiological and pathological activities of bone. However, the association between the abnormal expression of PTHrP and FD, as well as its underlying mechanism, remains unclear. In this study, we discovered that FD patient-derived bone marrow stromal cells (FD BMSCs) expressed significantly higher levels of PTHrP during osteogenic differentiation and exhibited greater proliferation capacity but impaired osteogenic ability compared to normal control patient-derived BMSCs (NC BMSCs). Continuous exogenous PTHrP exposure on the NC BMSCs promoted the FD phenotype in both in vitro and in vivo experiments. Through the PTHrP/cAMP/PKA axis, PTHrP could partially influence the proliferation and osteogenesis capacity of FD BMSCs via the overactivation of the Wnt/β-Catenin signaling pathway. Furthermore, PTHrP not only directly modulated cAMP/PKA/CREB transduction but was also demonstrated as a transcriptional target of CREB. This study provides novel insight into the possible pathogenesis involved in the FD phenotype and enhances the understanding of its molecular signaling pathways, offering theoretical evidence for the feasibility of potential therapeutic targets for FD.

A Rare Skeletal Disorder, Fibrous Dysplasia: A Review of Its Pathogenesis and Therapeutic Prospects

“…Considering that the cAMP signaling pathway is a key intracellular signaling pathway involved in a wide range of physiological processes, including metabolism, cellular growth, and gene expression, its dysregulation can bring about devastating consequences to cell function, as implicated in a variety of diseases. As is the case with FD, the huge increase in cAMP level causes the cAMP-PKA-CREB pathway to be under perpetual stimulation via autocrine and paracrine actions of parathyroid hormone-related protein (PTHrP) by FD-derived BMSCs and osteoprogenitor cells [52,53]. High levels of PTHrP were detected both intracellularly and extracellularly, even in the late stages of osteogenic differentiation.…”

Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype

“…At the forefront of FD pathogenesis lies the perturbation of osteogenic differentiation, resulting in the entrapment of stromal cells in a pre-osteoblastic state. The maturation of pre-osteoblasts, pivotal for normal bone formation, is arrested in FD, leading to an accumulation of undifferentiated cells with dysregulated activities [4]. These cells express pro-fibrotic factors like transforming growth factor beta (TGFβ), collagen type 1 alpha 1 chain (COL1A1), collagen type 3 alpha 1 chain (COL3A1), procollagen lysine 2-oxoglutarate 5-dioxygenase (PLOD), and periostin (POSTN), which contribute to aberrant ECM production and deposition for the formation of dense fibrotic tissue [5][6][7].…”