Related Experiment Video
Updated: Jul 15, 2026
A Simple Pit Assay Protocol to Visualize and Quantify Osteoclastic Resorption In Vitro
Published on: June 16, 2022
Constitutively active parathyroid hormone receptor signaling in cells in osteoblastic lineage suppresses mechanical
Noriaki Ono1, Kazuhisa Nakashima, Ernestina Schipani
1Department of Molecular Pharmacology, Medical Research Institute, Graduate School, Tokyo Medical and Dental University, and Endocrine Unit, Massachusetts General Hospital, Boston 02114, USA.
Abstract:
Multiple signaling pathways participate in the regulation of bone remodeling, and pathological negative balance in the regulation results in osteoporosis. However, interactions of signaling pathways that act comprehensively in concert to maintain bone mass are not fully understood. We investigated roles of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts in unloading-induced bone loss using transgenic mice. Hind limb unloading by tail suspension reduced bone mass in wild-type mice. In contrast, signaling by constitutively active PTH/PTHrP receptor (caPPR), whose expression was regulated by the osteoblast-specific Col1a1 promoter (Col1a1-caPPR), suppressed unloading-induced reduction in bone mass in these transgenic mice. In Col1a1-caPPR transgenic (Tg) mice, hind limb unloading suppressed bone formation parameters in vivo and mineralized nodule formation in vitro similarly to those observed in wild-type mice. In addition, serum osteocalcin levels and mRNA expression levels of type I collagen, Runx2 and Osterix in bone were suppressed by unloading in both wild-type mice and Tg mice. However, in contrast to unloading-induced enhancement of bone resorption parameters in wild-type mice, Col1a1-caPPR signaling suppressed, rather than enhanced, osteoclast number and osteoclast surface as well as urinary deoxypyridinoline excretion upon unloading. Col1a1-caPPR signaling also suppressed mRNA expression levels of RANK and c-fms in bone upon unloading. Although the M-CSF and monocyte chemoattractant protein 1 (MCP-1) mRNA levels were enhanced in control Tg mice, these levels were suppressed in unloaded Tg mice. These results indicated that constitutive activation of PTH/PTHrP receptor signaling in osteoblastic cells suppresses unloading-induced bone loss specifically through the regulation of osteoclastic activity.
Insights
Constitutive activation of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts prevents unloading-induced bone loss by suppressing osteoclast activity. This finding offers insights into maintaining bone mass during reduced mechanical loading.
Area of Science:
- Bone Biology
- Skeletal Physiology
- Cell Signaling
Background:
- Bone remodeling is regulated by complex signaling pathways, with imbalances leading to osteoporosis.
- The precise interactions of signaling pathways maintaining bone mass under mechanical stress are not fully elucidated.
Purpose of the Study:
- To investigate the role of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts during unloading-induced bone loss.
- To determine if constitutive activation of PTH/PTHrP receptor signaling can mitigate bone loss caused by reduced mechanical loading.
Main Methods:
- Utilized transgenic mice with osteoblast-specific expression of a constitutively active PTH/PTHrP receptor (Col1a1-caPPR).
- Assessed bone mass, bone formation, and bone resorption parameters in wild-type and transgenic mice subjected to hind limb unloading.
- Analyzed gene expression of key bone remodeling markers (e.g., RANK, c-fms, M-CSF, MCP-1) and bone formation markers (e.g., type I collagen, Runx2, Osterix).
Main Results:
- Hind limb unloading reduced bone mass in wild-type mice but not in Col1a1-caPPR transgenic mice.
- While bone formation markers were suppressed by unloading in both groups, Col1a1-caPPR signaling counteracted the unloading-induced increase in bone resorption.
- Specifically, osteoclast number, surface, and urinary deoxypyridinoline excretion were suppressed by caPPR signaling upon unloading, alongside reduced RANK and c-fms expression.
Conclusions:
- Constitutive activation of PTH/PTHrP receptor signaling in osteoblasts effectively suppresses unloading-induced bone loss.
- This protective effect is primarily mediated by the regulation of osteoclastic activity, rather than direct enhancement of bone formation under unloading conditions.
Related Concept Videos
01:31Osteoclasts in Bone Remodeling
01:17Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...
01:40Bone Remodeling
01:21Skeleton and Calcium Homeostasis
00:59The Parathyroid Glands
Oxyphil cells, whose functions remain elusive, emerge during late puberty, adding a layer of complexity to the parathyroid gland's intricacies. In contrast, principal parathyroid cells undertake a vital role by producing...
01:29Bone Disorders
Bone deposition is also affected by the levels of sex hormones like estrogen and testosterone that promote osteoblast activity and bone matrix synthesis. When the level of these hormones decreases due to aging, it causes a reduction in bone deposition. As a result, bone resorption by osteoclasts...