Understanding the balance between osteogenesis and bone marrow adipogenesis in the aetiology of bone disease in experimental chronic kidney disease

Abstract

Chronic kidney disease–mineral and bone disorder (CKD-MBD) involves irreversible renal impairment that disrupts mineral balance and leads to skeletal complications collectively known as renal osteodystrophy (ROD). Increased bone marrow adipose tissue (BMAT) is a consistent feature in both patients and animal models of CKD, although its regulation remains unclear. Elevated levels of the Wnt signalling inhibitors sclerostin and dickkopf-1 (DKK1) have been implicated, as they suppress osteogenesis while promoting adipogenesis.

This study examined the relationship between BMAT accumulation and bone structure in CKD, with a focus on whether disease progression alters bone marrow mesenchymal stromal cell (BMSC) fate commitment to osteogenic or adipogenic precursors and their subsequent differentiation into mature osteoblasts or adipocytes. I further examined the effects of CKD-related factors—including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), phosphate, sclerostin, and indoxyl sulfate—on BMSC differentiation.

Furthermore, I evaluated whether dual inhibition of sclerostin and DKK1 with a bispecific antibody could prevent bone loss and limit BMAT expansion in a CKD mouse model.

Eight-week-old male C57BL/6J mice were fed a 0.2% adenine-supplemented diet for up to 5-weeks to induce CKD, while control mice received the same diet without adenine. CKD onset was confirmed by elevated plasma blood urea nitrogen, creatinine, PTH and FGF23 from week 3. After 5-weeks, trabecular bone mineral density and microarchitecture were significantly reduced, and cortical bone area and thickness declined as early as week 3. BMAT in the proximal tibia increased progressively, showing a significant rise by week 5 and was negatively correlated with trabecular bone volume. In early CKD (weeks 1–2), BMSCs exhibited greater adipogenic capacity, although the proportions of osteogenic and adipogenic progenitors were unchanged. In vitro, low doses of PTH enhanced osteogenesis, while indoxyl sulfate impaired both osteogenic and adipogenic differentiation; FGF23, phosphate, and sclerostin had no direct effects. Treatment with a bispecific antibody targeting sclerostin and DKK1 for 6-weeks improved trabecular and cortical bone parameters and prevented BMAT expansion in CKD mice.

In summary, BMAT accumulation during CKD progresses with disease duration and is not driven by early changes in precursor populations. Systemic CKD factors may modulate stromal cell fate over time, and dual inhibition of sclerostin and DKK1 represents a potential therapeutic strategy for the maintenance of bone health in CKD-MBD.