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

Abstract

In murine models, glucocorticoids decrease preosteoclast (POC) platelet-derived growth factor type BB (PDGF-BB), reducing migration of endothelial precursor and osteoprogenitor cells, impairing skeletal angiogenesis and osteogenesis. To explore translation to humans, we conducted a case-control study on Duchenne Muscular Dystrophy (DMD) youth treated with chronic glucocorticoids with or without osteoporosis relative to healthy controls. We quantified factors from serum (PDGF-BB, VEGF, angiogenin) by ELISA and peripheral blood mononuclear cell (PBMC) subpopulations as surrogates of POCs (CD14+/Stro-1-/CD105-), osteoprogenitor cells (Stro-1+/CD105+/CD14-/CD45-), and endothelial/hematopoietic progenitor cells (CD34+/CD14-/Stro-1-/CD105-) by flow cytometry to determine association with fractures. The mean fluorescence intensity (MFI) of CD140b (PDGF receptor beta) was also quantitated. People with DMD, aged 8-20-years, were stratified by fractures, including prior and subsequent fractures relative to biospecimen collection date. Healthy controls were age- and sex-matched. Differences between groups were assessed with one-way ANOVA with post-hoc Tukey's test, simple linear regression correlation between factors, retrospective fractures by Kendall Tau correlation, and prospective fractures by bivariable and multivariable accelerated time failure (AFT) 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 concentrations of serum PDGF-BB and percentages of circulating POCs, SPCs, and CD34+ cells in people with DMD treated with chronic glucocorticoids relative to healthy controls. Circulating CD34+ cell percentage positively correlated with PDGF-BB concentration, similar to murine models. A lower percentage of circulating SPCs and CD140b MFI was associated with increased number of retrospective fractures by Kendall Tau correlation. After a mean follow-up of 2.23 years, 19 of the 24 people with DMD sustained a subsequent fracture. A higher PDGF-BB concentration, and percent of POC, SPCs, and CD34+ cells were associated with a longer time to next fracture by AFT bivariable models. After controlling for covariates potentially associated with fracture risk, the percentage of CD34+ cells continued to be associated with a prolonged time to next fracture. Circulating CD34+ cells may thus be a potential biomarker to predict acute fracture risk in young people with DMD on chronic glucocorticoids.