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Mesenchymal stem cells in the treatment of osteogenesis imperfecta.

ABSTRACT: Osteogenesis imperfecta (OI) is a disease caused by mutations in different genes resulting in mild, severe, or lethal forms. With no cure, researchers have investigated the use of cell therapy to correct the underlying molecular defects of OI. Mesenchymal stem cells (MSCs) are of particular interest because of their differentiation capacity, immunomodulatory effects, and their ability to migrate to sites of damage. MSCs can be isolated from different sources, expanded in culture, and have been shown to be safe in numerous clinical applications. This review summarizes the preclinical and clinical studies of MSCs in the treatment of OI. Altogether, the culmination of these studies show that MSCs from different sources: 1) are safe to use in the clinic, 2) migrate to fracture sites and growth sites in bone, 3) engraft in low levels, 4) improve clinical outcome but have a transient effect, 5) have a therapeutic effect most likely due to paracrine mechanisms, and 6) have a reduced therapeutic potential when isolated from patients with OI.

SUBMITTER: Lang E

PROVIDER: S-EPMC9892307 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells in the treatment of osteogenesis imperfecta.

Lang Erica E Semon Julie A JA

Cell regeneration (London, England) 20230202 1

Osteogenesis imperfecta (OI) is a disease caused by mutations in different genes resulting in mild, severe, or lethal forms. With no cure, researchers have investigated the use of cell therapy to correct the underlying molecular defects of OI. Mesenchymal stem cells (MSCs) are of particular interest because of their differentiation capacity, immunomodulatory effects, and their ability to migrate to sites of damage. MSCs can be isolated from different sources, expanded in culture, and have been s ...[more]

PMID: 36725748

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Project description:BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-β signaling is a driver pathogenic mechanism in OI. Anti-TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Dataset Information

Mesenchymal stem cells in the treatment of osteogenesis imperfecta.

Publications

Mesenchymal stem cells in the treatment of osteogenesis imperfecta.

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