New insights into bone pathology through a transcriptomic profiling of an osteoblast model of Gaucher disease

Although up to 90% of Gaucher Disease (GD) patients report bone symptoms, the molecular basis underlying the contribution of osteoblasts in bone pathology remains poorly understood. To identify potential molecular players in this process, we developed and characterized a new model of GD osteoblasts by knocking out (KO) the GBA1 gene in the SaOS cell line and subsequently studied its transcriptional profile. SaOS GBA1 KO cells showed reduced matrix deposition compared with wild-type cells and enhanced induction of osteoclastogenesis, likely through increased release of the receptor activator of NF-KB ligand (RANKL). By performing RNA sequencing, we identified several differentially expressed genes involved in bone cell maturation and differentiation, matrix composition, and osteogenesis. Among these, three genes encoding for negative regulators of osteogenesis ( RORB , CDK6 , and IGFBP5 ) were markedly overexpressed. By silencing them, we partially restored the expression levels of alkaline phosphatase, pro-α1 chain of collagen type I, RANKL, osteoprotegerin, and sclerostin encoding genes. Altogether, our findings support a direct role of osteoblast dysfunction in GD-associated bone pathology and identify potential molecular targets for future therapeutic development.