Abstract
Osteoporosis or osteopenia are common clinical manifestations of sickle cell disease (SCD) with unclear mechanisms. Since senescence of circulating neutrophil can be modulated by signals derived from intestinal microbiome and neutrophils are abundant in bone marrow and can regulate osteoblasts and osteoclasts, we examined whether gut microbiome contributes to bone loss in SCD mice. SCD and their littermates control mice were treated with antibiotics to deplete gut microbiome. At the end of 7 weeks treatment, serum was collected for biochemistry marker measurements. Bone mass and remodeling were evaluated by dual beam X-ray absorptiometry, micro-computed tomography, and histomorphometry. Bone-related genes in tibia and barrier marker genes in the small intestine were analyzed by quantitative PCR. Antibiotic treatment rescued increased intestinal inflammatory cytokine marker genes (Tnfα, IL17, Ifnγ) expression, rescued decreased intestinal barrier marker genes (claudin 3 and claudin 15) expression, and rescued increased serum cytokines (IFNγ, IL27, IL10) in SCD mice. Antibiotic significantly improved decreased bone mass in SCD mice mainly through enhanced osteoblast function and increased osteoblast-related genes (Runx2 and Igf1) expression in SCD mice. Our findings support that increased bacteria load augments antigenic load traversing the impaired intestinal barrier through inflammation, leading to increased inflammatory cytokines, impaired osteoblast function, and bone loss in SCD mice.
Highlights
Effective treatment options for sickle cell bone disease are lacking and there are no consensus guidelines for the use of well-established anti-osteoporotic therapies in sickle cell disease (SCD) patients[2]
Since SCD is associated with chronic inflammation[10,17,18], and inflammation in the intestine can decrease intestinal barrier integrity and increase the antigenic load traversing the intestinal barrier[19], we measured mRNA levels of inflammatory cytokines Tnfα, IL17, and Ifnγ, and gap junction protein marker genes, claudin 3 and claudin 15, in small intestine of 6-month-old single-housed male mice
In the present study using the Townes SCD mouse model that phenocopies human SCD, we demonstrated a significant reduction in BMD and bone mineral content (BMC) in SCD male mice compared to healthy Ctrl mice
Summary
Effective treatment options for sickle cell bone disease are lacking and there are no consensus guidelines for the use of well-established anti-osteoporotic therapies in SCD patients[2]. Depletion of intestinal microbiome decreased neutrophil senescence in circulation and partially rescued the liver and spleen damage in SCD mice[10]. Bone marrow neutrophilia decrease osteoblast number[15,16], we examined whether there are changes in intestinal microbiome and whether this is related to bone loss in SCD mice in vivo. Depletion of gut microbiome partially rescued bone loss in SCD mice. These suggest that microbiome modification might be a potential adjuvant therapy for sickle cell bone disease
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