Impaired Osteocyte Maturation in the Pathogenesis of Renal Osteodystrophy

Abstract

Pediatric renal osteodystrophy is characterized by skeletal mineralization defects but the role of osteoblast and osteocyte maturation in the pathogenesis of these defects is unknown. We evaluated markers of osteocyte maturation (early osteocytes: e11/gp38; mature osteocytes: MEPE) and programmed cell death (TUNEL) in iliac crest of healthy controls and dialysis patients. We evaluated the relationship between numbers of FGF23-expressing osteocytes and histomorphometric parameters of skeletal mineralization. We confirmed that CKD causes intrinsic changes in bone cell maturation using an in vitro model of primary CKD osteoblasts. FGF23 co-localized with e11/gp38, suggesting that FGF23 is a marker of early osteocytes. Increased numbers of early osteocytes and decreased osteocyte apoptosis characterized CKD bone. Numbers of FGF23-expressing osteocytes were highest in patients with preserved skeletal mineralization indices and packets of matrix surrounding FGF23-expressing osteocytes appeared to have entered secondary mineralization. Primary CKD osteoblasts retained impaired maturation and mineralization characteristics in vitro. FGF23 did not affect primary osteoblast mineralization. Thus, CKD is associated with intrinsic changes in osteoblast and osteocyte maturation and FGF23 appears to mark a relatively early stage in osteocyte maturation. Improved control of renal osteodystrophy and of FGF23 excess will require further investigations into the pathogenesis of CKD-mediated osteoblast and osteocyte maturation failure.