Related Experiment Video
Updated: Aug 8, 2025
A Novel in vivo Gene Transfer Technique and in vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders
Published on: June 8, 2014
JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors
Shinya Yari1,2, Junichi Kikuta3,4,5, Hotaka Shigyo1
1Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, 565-0871, Japan.
Background:
Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging.
Methods:
Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts.
Results:
The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions.
Conclusions:
This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.
Insights
A Janus kinase (JAK) inhibitor, ABT-317, effectively reduces rheumatoid arthritis (RA) bone destruction by targeting both mature osteoclasts and their precursors. This dual action inhibits inflammation-driven bone loss, offering a promising therapeutic strategy for RA.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) involves chronic inflammation and bone destruction driven by osteoclasts.
- Janus kinase (JAK) inhibitors show promise in treating RA, but their bone-protective mechanisms are not fully understood.
- This study investigates the effects of a JAK inhibitor on osteoclasts and their precursors in inflammatory bone destruction.
Purpose of the Study:
- To elucidate the mechanism by which a JAK inhibitor mitigates bone destruction in inflammatory conditions.
- To examine the impact of a JAK inhibitor on the function and behavior of mature osteoclasts and osteoclast precursors.
- To identify specific molecular targets involved in the JAK inhibitor's bone-protective effects.
Main Methods:
- Utilized intravital multiphoton microscopy to observe osteoclast activity in transgenic mice with induced inflammatory bone destruction.
- Administered the selective JAK1 inhibitor, ABT-317, and analyzed its effects on osteoclasts and their precursors.
- Conducted RNA sequencing (RNA-Seq) to identify molecular pathways affected by the JAK inhibitor, including chemokine receptor expression.
Main Results:
- The JAK inhibitor ABT-317 suppressed bone resorption by inhibiting mature osteoclast function.
- ABT-317 also targeted the migration of osteoclast precursors to bone surfaces.
- RNA-Seq revealed suppressed Ccr1 expression on osteoclast precursors; a CCR1 antagonist mimicked the migratory inhibition and reduced bone destruction.
Conclusions:
- This study provides the first detailed pharmacological insights into how JAK inhibitors block inflammatory bone destruction.
- The JAK inhibitor exerts beneficial dual effects by acting on both mature osteoclasts and immature osteoclast precursors.
- Targeting Ccr1 on osteoclast precursors represents a key mechanism for the bone-protective effects of JAK inhibitors in RA.
More Related Videos
Related Concept Videos
01:31Osteoclasts in Bone Remodeling
01:40Bone Remodeling
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...
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...
01:25Role of Vitamins in Maintaining Bone Health
Vitamin A
Vitamin A is involved in the process of bone remodeling. Retinoic acid, the active metabolite of Vitamin A, has nuclear receptors in osteoblasts and osteoclasts, which are involved in bone remodeling.
Vitamin B12
Vitamin B12 acts as a cofactor during the formation of osteoblast-related proteins, such as osteocalcin. Vitamin B12 plays a role...
02:34Inhibition of Cdk Activity