Age‐related decline in osteoblastogenesis and 1α‐hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

Abstract

Summary With aging, there is a decline in bone mass and in osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro. Osteoblastogenesis can be stimulated with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and, in some hMSCs, by the precursor 25-hydroxyvitamin D3 (25OHD3). CYP27B1/1α-hydroxylase activates 25OHD3 and, to a variable degree, hMSCs express CYP27B1. In this study, we tested the hypotheses 1) that age affects responsiveness to 25OHD3 and expression/activity of CYP27B1 in hMSCs, and 2) that parathyroid hormone (PTH) upregulates CYP27B1 in hMSCs, as it does in renal cells. There were age-related declines in osteoblastogenesis (n=8, p=0.0286) and in CYP27B1 gene expression (n=27, r=−0.498; p=0.008) in hMSCs. Unlike hMSCs from young subjects (≤ 50-years), hMSCs from older subjects (≥ 55-years) were resistant to 25OHD3 stimulation of osteoblastogenesis. PTH1-34 (100 nM) provided hMSCs with responsiveness to 25OHD3 (p=0.0313, Wilcoxon matched pairs test) and with two episodes of increased 1,25(OH)2D3 synthesis, of CREB activation, and of CYP27B1 upregulation. Both increases in CYP27B1 expression by PTH were obliterated by CREB-siRNA or KG-501 (which specifically inhibits the downstream binding of activated CREB). Only the second period of CREB signaling was diminished by AG1024, an inhibitor of insulin-like growth factor-I receptor kinase. Thus, PTH stimulated hMSCs from elders with responsiveness to 25OHD3 by upregulating expression/activity of CYP27B1 and did so through CREB and IGF-I pathways.

Sarcopenia in post-menopausal women: Is there any role for vitamin D?

“…Vitamin D regulates the calcium-mediated functions of muscle, such as contraction, mitochondrial function and insulin sensitivity [15]. Of note, VDR and 1-alpha-hydroxylase enzyme are expressed in skeletal muscles [37] and their expression seems to decline with age [38,39]. Vitamin D signaling via VDR regulates gene transcription and activates intracellular signaling pathways involved in calcium metabolism, and might therefore be involved in myoblast proliferation and differentiation [40,41].…”

Histone deacetylation mediates the rejuvenation of osteoblastogenesis by the combination of 25(OH)D3 and parathyroid hormone in MSCs from elders

“…Osteoblastogenesis is also stimulated by 25-hydroxyvitamin D [25(OH)D 3 ] [2], an effect that requires conversion to 1α, 25(OH) 2 D 3 by 25-hydroxyvitamin D 3 1α-hydroxylase (CYP27B1) [3]. CYP27B1 in hMSCs is upregulated by 25OHD [2], IGF-I [2], and PTH [4] and is downregulated by 1α, 25(OH) 2 D [2] and with age of the subject [4]. These findings support an autocrine/paracrine role of vitamin D metabolism in osteoblastogenesis of hMSCs.…”

“…These findings support an autocrine/paracrine role of vitamin D metabolism in osteoblastogenesis of hMSCs. There are striking age-associated declines in baseline osteoblast differentiation of hMSCs [4–7], as well as in in vitro stimulation of osteoblastogenesis by 1α, 25(OH) 2 D 3 [8], 25(OH)D 3 [4], and PTH (1-34) [9]. The combination of 25(OH)D 3 and PTH-pretreatment, however, rejuvenated osteoblast differentiation in hMSCs from elders [4].…”

“…There are striking age-associated declines in baseline osteoblast differentiation of hMSCs [4–7], as well as in in vitro stimulation of osteoblastogenesis by 1α, 25(OH) 2 D 3 [8], 25(OH)D 3 [4], and PTH (1-34) [9]. The combination of 25(OH)D 3 and PTH-pretreatment, however, rejuvenated osteoblast differentiation in hMSCs from elders [4]. The studies herein test the hypotheses 1) that VDR is required for actions of 1α, 25(OH) 2 D 3 in hMSCs, 2) that simultaneous treatment with PTH and 1α, 25(OH) 2 D 3 stimulates osteoblastogenesis, and 3) that an epigenetic mechanism mediates the rejuvenation of osteoblastogenesis by a combination of 25(OH)D 3 and PTH.…”

Vitamin D, muscle and bone: Integrating effects in development, aging and injury

“…In addition, Cyp27b1 levels drop in aged bone cells and MSCs, blunting their responses to 25OHD (Anderson et al, 2005;Geng et al, 2011a). Clinically, 25OHD levels correlate more tightly with bone parameters in the elderly than 1,25(OH)2D, also supporting an effect of Cyp27b1 in skeletal aging .…”