Related Experiment Video

Updated: Sep 13, 2026

A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation
09:37

A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation

Published on: March 14, 2018

13.9K

Regulation of osteoclast function via Rho-Pkn3-c-Src pathways

Shunsuke Uehara1, Nobuyuki Udagawa2, Yasuhiro Kobayashi3

  • 1Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan.

Journal of Oral Biosciences
|August 11, 2019
PubMed
Abstract

Insights

Wnt5a-Ror2 signaling enhances osteoclast bone resorption via the Daam2-Rho-Pkn3-c-Src pathway. Pkn3 inhibition may treat osteoporosis and inflammatory bone diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Bone Biology

Background:

  • Wnt signaling pathways are crucial in bone metabolism, with canonical and non-canonical pathways having distinct roles.
  • Previous research indicated Wnt5a-receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling promotes osteoclast differentiation.
  • The precise function of Wnt5a-Ror2 signaling in mature osteoclast activity remained undetermined.

Purpose of the Study:

  • To elucidate the role of Wnt5a-Ror2 signaling in osteoclast function and bone resorption.
  • To identify downstream effectors and molecular mechanisms involved in Wnt5a-Ror2-mediated osteoclast activity.

Main Methods:

  • Utilized osteoclast-specific Ror2-deficient mice (Ror2ΔOCL/ΔOCL) and protein kinase N3 (Pkn3)-deficient mice.
  • Investigated the activation of Rho and its downstream effectors, including Pkn3, in osteoclasts.
  • Analyzed the interaction of Pkn3 with c-Src and Pyk2 and its impact on kinase activity.

Main Results:

  • Osteoclast-specific Ror2 deficiency led to increased trabecular bone mass due to reduced osteoclast bone-resorbing activity.
  • Wnt5a-Ror2 signaling activated Rho via dishevelled-associated activator of morphogenesis 2 (Daam2) in osteoclasts.
  • Pkn3 expression increased during osteoclast differentiation, and Pkn3 deficiency also resulted in greater trabecular bone mass.
  • Pkn3 directly bound to c-Src and Pyk2, enhancing c-Src kinase activity in a Wnt5a-Ror2-dependent manner, which is essential for osteoclast bone resorption.

Conclusions:

  • Wnt5a-Ror2 signaling stimulates osteoclast bone-resorbing activity through the Daam2-Rho-Pkn3-c-Src pathway.
  • Pkn3 is a key mediator in Wnt5a-Ror2 signaling's effect on osteoclast function.
  • Targeting Pkn3 presents a potential therapeutic strategy for osteoporosis and inflammatory bone diseases.
Keywords:
Actin cytoskeletonBone resorptionOsteoclastProtein-serine-threonine kinasesWnt5a protein

More Related Videos

Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model08:42

Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model

Published on: July 2, 2020

4.8K
A Simple Pit Assay Protocol to Visualize and Quantify Osteoclastic Resorption In Vitro07:03

A Simple Pit Assay Protocol to Visualize and Quantify Osteoclastic Resorption In Vitro

Published on: June 15, 2022

6.9K

Related Concept Videos

Bone Remodeling01:40

Bone Remodeling

Bone remodeling is a continuous and balanced process of bone resorption by osteoclasts and bone formation by osteoblasts. In adults, it helps maintain bone mass and calcium homeostasis. While mechanical stress can stimulate turnover as part of the normal maintenance and reparative process, several hormones also regulate bone remodeling.
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Osteoclasts in Bone Remodeling01:31

Osteoclasts in Bone Remodeling

Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during bone...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...