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SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling
Xudong Xie1,2, Liangcong Hu1,2, Bobin Mi1,2
1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
With the worldwide aging population, the prevalence of osteoporosis is on the rise, particularly the number of postmenopausal women with the condition. However, the various adverse side effects associated with the currently available treatment options underscore the need to develop novel therapies. In this study, we investigated the use of AQX-1125, a novel clinical-stage activator of inositol phosphatase-1 (SHIP1), in ovariectomized (OVX) mice, identifying a protective role. We then found that the effect was likely due to increased osteogenesis and mineralization and decreased osteoclastogenesis caused by AQX-1125 in a time- and dose-dependent manner. The effect against OVX-induced bone loss was identified to be SHIP1-dependent as pretreatment of BMSCs and BMMs with SHIP1 RNAi could greatly diminish the osteoprotective effects. Furthermore, SHIP1 RNAi administration in vivo induced significant bone loss and decreased bone mass. Mechanistically, AQX-1125 upregulated the expression level and activity of SHIP1, followed upregulating the phosphorylation levels of PI3K and Akt to promote osteoblast-related gene expressions, including Alp, cbfa1, Col1a1, and osteocalcin (OCN). NF-κB signaling was also inhibited through suppression of the phosphorylation of IκBα and P65 induced by RANKL, resulting in diminished osteoclastogenesis. Taken together, our results demonstrate that AQX-1125 may be a promising candidate for preventing and treating bone loss.
Insights
AQX-1125, a novel therapy, shows promise in treating osteoporosis by activating SHIP1 (spleen tyrosine kinase). This treatment promotes bone formation and reduces bone loss in ovariectomized mice, offering a potential new therapeutic avenue.
Area of Science:
- Biomedical research
- Pharmacology
- Bone biology
Background:
- Osteoporosis prevalence is increasing globally, especially in postmenopausal women.
- Current osteoporosis treatments have adverse side effects, necessitating novel therapeutic strategies.
- Inositol phosphatase-1 (SHIP1) plays a role in bone metabolism.
Purpose of the Study:
- To investigate the potential of AQX-1125, a SHIP1 activator, in treating osteoporosis.
- To elucidate the mechanism of action of AQX-1125 in bone loss models.
Main Methods:
- Utilized ovariectomized (OVX) mouse models to simulate postmenopausal osteoporosis.
- Administered AQX-1125 and assessed its effects on bone density, osteogenesis, and osteoclastogenesis.
- Employed small interfering RNA (siRNA) targeting SHIP1 to confirm the drug's mechanism of action.
- Analyzed molecular pathways including PI3K/Akt and NF-κB signaling.
Main Results:
- AQX-1125 demonstrated a protective effect against OVX-induced bone loss in a time- and dose-dependent manner.
- The observed osteoprotective effects were confirmed to be SHIP1-dependent.
- AQX-1125 treatment increased osteoblast activity and mineralization while decreasing osteoclast formation.
- Mechanistically, AQX-1125 upregulated SHIP1, PI3K, and Akt, promoting osteoblast gene expression and inhibiting NF-κB signaling.
Conclusions:
- AQX-1125 shows significant potential as a novel therapeutic agent for preventing and treating osteoporosis.
- The drug's efficacy is mediated through the SHIP1 pathway, enhancing bone formation and inhibiting bone resorption.
- Further research into AQX-1125 could lead to improved treatments for bone loss conditions.
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