Abstract
BackgroundOsteocytic protein expression is dysregulated in CKD and is affected by changes in mineral metabolism; however the effects of active vitamin D sterol therapy on osteocyte protein expression in advanced CKD is unknown.MethodsEleven pediatric patients with end stage kidney disease underwent bone biopsy, were treated for 8 months with doxercalciferol, and then underwent a second bone biopsy. Bone expression of fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), and sclerostin were determined by immunohistochemistry and quantified by Ariol Scanning. Western blot analysis and qRT-PCR was performed on bone abstracts of a subset of study subjects to determine the nature (i.e. size) of FGF23 and DMP1 in bone before and after therapy.ResultsAs assessed by immunohistochemistry, bone FGF23, DMP1 and sclerostin protein all increased with therapy. In the case of FGF23, this increase was due to an increase in the full-length molecule without the appearance of FGF23 fragments. DMP1 was present primarily in its full-length form in healthy controls while 57kDa and 37kDa fragments of DMP1 were apparent in bone of dialysis patients at baseline and the 57 kDa appeared to decrease with therapy.ConclusionMarked changes in osteocytic protein expression accompany doxercalciferol therapy, potentially impacting bone mineralization and the skeletal response to PTH. The effects of these bone changes on long-term outcomes remain to be determined.
Highlights
Recent studies have identified that bone expression of fibroblast growth factor 23 (FGF23) increases early in the course of chronic kidney disease (CKD)[1] and is linked to abnormalities in skeletal mineralization, [2] redefining osteocytes as endocrine cells which generate hormones that affect both bone and the cardiovascular system.[2–4] PTH stimulates FGF23 production via activation of the nuclear receptor related 1 protein (Nurr1) [5] and potentially via suppression of sclerostin;[6] increased expression of FGF23 in CKD occurs prior to detectable changes in circulating PTH concentration.[1, 2] skeletal sclerostin expression increases in early CKD despite normal serum PTH levels[7] and continues to be increased even in end-stage kidney disease, despite elevated circulating PTH values.[8]
Bone FGF23, dentin matrix protein 1 (DMP1) and sclerostin protein all increased with therapy
In the case of FGF23, this increase was due to an increase in the fulllength molecule without the appearance of FGF23 fragments
Summary
Recent studies have identified that bone expression of fibroblast growth factor 23 (FGF23) increases early in the course of chronic kidney disease (CKD)[1] and is linked to abnormalities in skeletal mineralization, [2] redefining osteocytes as endocrine cells which generate hormones that affect both bone and the cardiovascular system.[2–4] PTH stimulates FGF23 production via activation of the nuclear receptor related 1 protein (Nurr1) [5] and potentially via suppression of sclerostin;[6] increased expression of FGF23 in CKD occurs prior to detectable changes in circulating PTH concentration.[1, 2] skeletal sclerostin expression increases in early CKD despite normal serum PTH levels[7] and continues to be increased even in end-stage kidney disease, despite elevated circulating PTH values.[8]. Recent studies have identified that bone expression of fibroblast growth factor 23 (FGF23) increases early in the course of chronic kidney disease (CKD)[1] and is linked to abnormalities in skeletal mineralization, [2] redefining osteocytes as endocrine cells which generate hormones that affect both bone and the cardiovascular system.[2–4]. PTH stimulates FGF23 production via activation of the nuclear receptor related 1 protein (Nurr1) [5] and potentially via suppression of sclerostin;[6] increased expression of FGF23 in CKD occurs prior to detectable changes in circulating PTH concentration.[1, 2]. Skeletal sclerostin expression increases in early CKD despite normal serum PTH levels[7] and continues to be increased even in end-stage kidney disease, despite elevated circulating PTH values.[8]. Osteocytic protein expression is dysregulated in CKD and is affected by changes in mineral metabolism; the effects of active vitamin D sterol therapy on osteocyte protein expression in advanced CKD is unknown
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