Circulating CD34-positive cells are associated with prolonged time to fracture in people with Duchenne muscular dystrophy on chronic glucocorticoids.

Abstract

Glucocorticoids decrease preosteoclast (POC) platelet-derived-growth-factor-type-BB (PDGF-BB), reducing migration of endothelial and osteo-progenitor cells, impairing skeletal angiogenesis and osteogenesis in mice. To explore human translation, we conducted a case-control study on Duchenne muscular dystrophy (DMD) youth treated with chronic glucocorticoids (n=24) relative to healthy controls (n=13) to explore the association of PDGF-BB, VEGF, angiogenin concentration and peripheral blood mononuclear cell (PBMC) subpopulations as surrogates of POCs (CD14+/Stro-1-/CD105-), skeletal progenitor cells (SPCs: Stro-1+/CD105+/CD14-/CD45-), and endothelial/hematopoietic progenitor cells (CD34+/CD14-/Stro-1-/CD105-) and CE140b mean fluorescence intensity (MFI) to fracture. People with DMD (8-20 years), were stratified by prior and subsequent fractures relative to biospecimen collection. Healthy controls were age- and sex-matched. Differences between groups were assessed with one-way ANOVA with post-hoc Tukey's test, retrospective fractures by Kendall Tau correlation, and prospective fractures by bivariable and multivariable accelerated time failure models. Baseline characteristics between groups were similar, though people with DMD were shorter relative to healthy controls, and in the DMD groups, those with prior fractures had a longer duration of glucocorticoid therapy. We noted decreased PDGF-BB concentration and percentages of circulating POCs, SPCs, and CD34+ cells in people with DMD relative to healthy controls. Circulating CD34+ cell percentage positively correlated with PDGF-BB concentration, similar to murine models. Lower percentage of circulating SPCs and CD140b MFI was associated with increased number of retrospective fractures. After a mean follow-up of 2.23 yr, 79% of people with DMD sustained a subsequent fracture. Higher PDGF-BB concentration and percent of POC, SPCs, and CD34+ cells were associated with a longer time to next fracture. After controlling for covariates of fracture risk, increased percentage of CD34+ cells continued to be associated with prolonged time to fracture. Circulating CD34+ cells may thus be a potential biomarker to predict acute fracture risk in young people with DMD on chronic glucocorticoids.