Bone is a metabolically active tissue that is continuously remodeled throughout life. Osteocytes, the most abundant cells in bone, regulate bone homeostasis in response to hormonal and mechanical cues. Parathyroid hormone (PTH), a calciotropic hormone secreted from the parathyroid glands, has been widely used in the clinic to treat age-related osteoporosis. PTH acts on cells of the osteoblast lineage, including osteocytes, by signaling via the PTH receptor (PPR) to promote bone formation. However, the role of PPR signaling in osteocytes during aging has not been investigated. The hypothesis of this study is that PPR signaling in osteocytes plays a key role in maintaining skeletal health in aging mice. To address this hypothesis, mice in which the PPR was ablated in mature osteoblasts/osteocytes (Dmp1-Cre+;PPRfl/fl or Dmp1-PPRKO) were used to study their skeletal phenotype at 4 and 13 months of age. Compared to control littermates (Dmp1-Cre–;PPRfl/fl), Dmp1-PPRKO animals displayed age-dependent osteopenia due to reduced osteoblast activity and increased osteoclast numbers and activity. These changes were associated with a significant decrease in osteoprogenitors and an increase in marrow adiposity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes was accompanied by a marked increase in serum sclerostin, RANKL-expressing marrow adipocytes, and early onset of oxidative stress in osteocytes. In vitro studies demonstrated that PTH protected osteocytes from oxidative stress-induced cell death by suppressing the intracellular accumulation of reactive oxygen species.
Mechanical forces are also important regulators of bone mass and quality. For instance, immobilization and reduced mechanical loading, such as prolonged bed rest or long-duration spaceflight, lead to bone loss or osteopenia due to reduced bone formation and increased bone resorption. Osteocytes are known to sense and transduce mechanical forces applied to the skeleton into biochemical signals. However, the exact molecular mechanism remains unclear. To unravel the mechanism by which osteocytes sense and respond to mechanical unloading, an osteocytic cell line, Ocy454, was exposed to microgravity (µG) conditions for 2, 4, or 6 days onboard the SpaceX Dragon-6 and the International Space Station. Global transcriptomic analysis demonstrated that µG leads to downregulation of key osteocytic marker genes compared to ground controls (1G), suggesting the impaired differentiation of osteocytes. Importantly, glycolysis was the most activated signaling pathway in osteocytes subjected to µG compared to 1G. Gene comparison analysis further identified a set of mechano-sensitive genes that are consistently regulated in multiple types of cells exposed to µG, suggesting a common, yet to be fully elucidated, genome-wide response to µG.
In summary, these studies demonstrated that osteocytes are highly regulated by PTH and mechanical forces. We found that PPR signaling in osteocytes is important for protecting the skeleton from age-induced osteopenia by promoting osteoblast’s bone-forming activity and mitigating osteoclast’s bone resorption. We also demonstrated that PTH protects osteocytes from oxidative stress. Finally, we showed that osteocytes respond to µG with an increase in glucose metabolism and oxygen consumption.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/45700 |
| Date | 25 February 2023 |
| Creators | Uda, Yuhei |
| Contributors | Divieti Pajevic, Paola |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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