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Inhibitor of protein kinase N3 suppresses excessive bone resorption in ovariectomized mice
Shunsuke Uehara1, Hideyuki Mukai2,3, Teruhito Yamashita4
1Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan.
Introduction:
The long-term inhibition of bone resorption suppresses new bone formation because these processes are coupled during physiological bone remodeling. The development of anti-bone-resorbing agents that do not suppress bone formation is urgently needed. We previously demonstrated that Wnt5a-Ror2 signaling in mature osteoclasts promoted bone-resorbing activity through protein kinase N3 (Pkn3). The p38 MAPK inhibitor SB202190 reportedly inhibited Pkn3 with a low Ki value (0.004 μM). We herein examined the effects of SB202190 on osteoclast differentiation and function in vitro and in vivo.
Materials And Methods:
Bone marrow cells were cultured in the presence of M-csf and GST-Rankl to differentiate into multinucleated osteoclasts. Osteoclasts were treated with increasing concentrations of SB202190. For in vivo study, 10-week-old female mice were subjected to ovariectomy (OVX). OVX mice were intraperitoneally administered with a Pkn3 inhibitor at 2 mg/kg or vehicle for 4 weeks, and bone mass was analyzed by micro-CT.
Results:
SB202190 suppressed the auto-phosphorylation of Pkn3 in osteoclast cultures. SB202190 significantly inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation. SB202190 reduced c-Src activity in osteoclast cultures without affecting the interaction between Pkn3 and c-Src. A treatment with SB202190 attenuated OVX-induced bone loss without affecting the number of osteoclasts or bone formation by osteoblasts.
Conclusions:
Our results showed that Pkn3 has potential as a therapeutic target for bone loss due to increased bone resorption. SB202190 is promising as a lead compound for the development of novel anti-bone-resorbing agents.
Insights
SB202190 effectively inhibits osteoclast activity and bone resorption by targeting Pkn3 signaling. This compound shows promise for treating bone loss without negatively impacting bone formation.
Area of Science:
- Bone Biology
- Pharmacology
- Osteoclast Biology
Background:
- Bone resorption and formation are coupled processes in bone remodeling.
- Current anti-resorptive agents can impede new bone formation.
- Wnt5a-Ror2 signaling in osteoclasts promotes bone resorption via Pkn3.
Purpose of the Study:
- To investigate the effects of SB202190, a p38 MAPK inhibitor, on osteoclast differentiation and function.
- To evaluate SB202190 as a potential therapeutic agent for bone loss.
Main Methods:
- Osteoclast differentiation from bone marrow cells in vitro.
- Treatment of osteoclasts with varying concentrations of SB202190.
- In vivo study using ovariectomized mice treated with SB202190 or vehicle.
Main Results:
- SB202190 suppressed Pkn3 auto-phosphorylation and osteoclast resorption pit formation.
- SB202190 reduced c-Src activity without altering Pkn3-c-Src interaction.
- SB202190 treatment attenuated ovariectomy-induced bone loss in mice.
Conclusions:
- Pkn3 is a viable therapeutic target for conditions involving excessive bone resorption.
- SB202190 demonstrates potential as a lead compound for developing new anti-bone-resorbing drugs.
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