Abstract
Aging is accompanied by osteopenia, characterized by reduced bone formation and increased bone resorption. Osteocytes, the terminally differentiated osteoblasts, are regulators of bone homeostasis, and parathyroid hormone (PTH) receptor (PPR) signaling in mature osteoblasts/osteocytes is essential for PTH-driven anabolic and catabolic skeletal responses. However, the role of PPR signaling in those cells during aging has not been investigated. The aim of this study was to analyze the role of PTH signaling in mature osteoblasts/osteocytes during aging. Mice lacking PPR in osteocyte (Dmp1-PPRKO) display an age-dependent osteopenia characterized by a significant decrease in osteoblast activity and increase in osteoclast number and activity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes is associated with an increase in serum sclerostin and a significant increase in osteocytes expressing 4-hydroxy-2-nonenals, a marker of oxidative stress. In Dmp1-PPRKO mice there was an age-dependent increase in p16Ink4a/Cdkn2a expression, whereas it was unchanged in controls. In vitro studies demonstrated that PTH protects osteocytes from oxidative stress-induced cell death. In summary, we reported that PPR signaling in osteocytes is important for protecting the skeleton from age-induced bone loss by restraining osteoclast’s activity and protecting osteocytes from oxidative stresses.
Highlights
Osteoporosis affects an estimated 200 million people worldwide and it becomes increasingly prevalent in the aging population [1, 2]
Taken together this data revealed a marked age-dependent trabecular bone loss in the absence of PTHrP receptor (PPR) signaling in mature osteoblasts/osteocytes
Bone formation rate (BFR) over bone volume (BFR/BV) was significantly decreased in dentin matrix protein 1 (Dmp1)-PPRKO at 4 months and mineral apposition rate (MAR) was significantly reduced in 13-month-old Dmp1-PPRKO mice compared to controls (Figure 2C–2D, Table 1). These results indicate that, in the absence of PPR signaling in mature osteoblasts/osteocytes, there is an age-dependent increase in osteoclast numbers and activity and ageindependent decrease in osteoblast activity resulting in increased bone resorption and bone loss
Summary
Osteoporosis affects an estimated 200 million people worldwide and it becomes increasingly prevalent in the aging population [1, 2]. PTH and PTHrP exert their anabolic and catabolic effects by binding and activating the PPR expressed on cells of the osteoblast lineage. This lineage comprises a variety of cells, from osteoprogenitors to mature osteoblasts and osteocytes; cellular targets of PTH actions are still not completely understood. Recent literature supports direct and indirect interactions of osteocytes with nearby cells, including osteoblasts, osteoclasts, and endothelial cells and with distant organs, such as kidneys and muscles, through various secreted molecules, including receptor-activator of nuclear factor-κB ligand (RANKL), fibroblast growth factor 23 (FGF23) and sclerostin [7,8,9,10,11,12,13]. Osteocytes may play important roles in diseases such as hypophosphatemic rickets, osteopenia, sclerosteosis, Van Buchem disease, and osteopetrosis [17,18,19]
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