Biochemical and Biophysical Research Communications
Osteoblastic differentiation of bone marrow mesenchymal stem cells in uremic rats
Introduction
Chronic kidney disease (CKD) is often complicated by disturbances in mineral metabolism that lead to the development of renal osteopathy, which is characterized by increased bone loss and bone fractures [1]. Serum parathyroid hormone (PTH) is elevated in CKD patients, and severe secondary hyperparathyroidism (SHPT) represents a high turnover bone disease that results in reduced bone density and increased risk of bone fracture [2,3]. The bone and mineral injury is referred to as chronic kidney disease-mineral and bone disorder (CKD-MBD), which frequently affects the quality of life, morbidity and mortality [4].
Bone marrow mesenchymal stem cells (BMSCs) are multipotent stem cells that have the ability to differentiate into osteoblasts and other cellular types, such as chondrocytes and adipocytes [5]. Osteogenesis takes place via a multi-step differentiation cascade that is thought to originate from multipotent mesenchymal cells, proceeding through osteoprogenitors and osteoblasts to generate mature bone osteocytes [6]. Whether MSCs proliferate as multipotent stem cells capable of differentiating in multiple mesenchymal lineages, or as committed progenitors of a particular lineage, is likely regulated by numerous growth factors, cytokines and hormones [7].
Many previous studies have shown that CKD with SHPT leads to increased progression of cardiovascular disease, vascular calcification, endothelial dysfunction, disorders of mineral and bone metabolism, including bone fracture, and a higher mortality rate [[8], [9], [10]]. However, it is unclear how the osteogenic differentiation of BMSCs can be achieved in the state of CKD and SHPT. In this study, we examined the characteristics of the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts in uremic rats with SHPT.
Section snippets
Animals
Study protocols were approved by the Showa University Animal Studies Committee in accordance with federal regulations. Eight-week-old male Sprague Dawley rats weighing 225–250 g were randomly assigned to three groups: (1) normal rats fed a standard diet (Nc + ND; n = 7), (2) 5/6 nephrectomized rats fed a standard diet (Nx + ND; n = 7) and (3) the 5/6 nephrectomized rats fed a high phosphorus diet (Nx + HP: n = 12). The standard diet contained 0.6% phosphate and the high phosphorus diet
Renal function and biochemical parameters
The biochemical data of the rats at 18 weeks of age are shown in Fig. 1. Compared with the Nc + ND rats, rats in the Nx + ND and Nx + HP groups showed significantly increased serum creatinine levels. Serum inorganic phosphate was higher level in the Nx + HP rats than that in the Nc + ND or Nx + ND rats. In contrast, serum calcium levels were lower level in the Nx + HP rats than in the Nc + ND or Nx + ND rats. Intact PTH and intact FGF-23 levels showed similar trends.
Bone histology and histomorphometry
Histological examination of
Discussion
The present study demonstrated that osteoblastic differentiation of MSCs from CKD model rats was suppressed compared with MSCs from normal rats. Furthermore, MSCs from SHPT model rats may exhibit even greater suppression of osteoblastic differentiation. In this study, MSCs from all groups of rats were incubated in the same osteogenic medium when osteoblastic differentiation of the MSCs was assessed.
In CKD, there is a broad range of bone turnover phenotypes, which are often categorized
Author contributions
TK, MM, KS, AY, HO, HH, AS and RK: were involved in the study concept. TK, MM and KS: were involved in the formal analysis; TK, MM, AY, HO, AS and RK: acquired funding; TK: investigated the study; TK, MM and RK: applied the methodology for the study; MM and HO: project administration; MM and HO: collection of the resources; MM and HO: supervision and validation of the study; TK: wrote the original manuscript; TK, MM, HO, HH and RK: reviewed and edited the original manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This work was supported in part by Grant-in-Aid for Young Scientists and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (19K17753, 19H03820, 18K19655, 18K09512, 19K18950, 18K08253, 17K09737), and by Grant for pathophysiological research conference in chronic kidney disease from the Kidney Foundation, Japan (JKFB18-17).
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Present address: Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1 Chigasakichuo, Yokohama, Kanagawa 224–8503, Japan.