Catalpol Promotes Osseointegration of Titanium Implants under Conditions of Type 2 Diabetes via AKT/GSK3β/FYN...

Catalpol (CA), a compound derived from the roots of Rehmannia glutinosa, is recognized for its anti-oxidative and anti-inflammatory properties. The current study aimed to evaluate the impact of CA on the osseointegration of titanium implants (TIs) in the context of type 2 diabetes and elucidate the underlying pharmacological mechanisms. MC3T3-E1 cells were incubated on the surface of titanium plates and exposed to various media for investigating osteoblast behaviors, as follows: regular medium, medium of high glucose and high lipid (HGHL) that simulates diabetic conditions, HGHL + CA medium, or HGHL + CA + LY294002 (an inhibitor of phosphoinositide 3-kinase or PI3K) medium. TIs were also surgically implanted into the femoral condyle defects in normal mice and mouse models of type 2 diabetes mellitus (T2DM). HGHL-induced oxidative stress was found to cause osteoblast dysfunction, accompanied by the inactivation of AKT/GSK3β/FYN pathway-mediated NRF2 signaling. However, CA administration effectively mitigated HGHL-induced oxidative stress and reactivated AKT/GSK3β/FYN/NRF2 signaling, resulting in the reversal of HGHL-induced dysfunctions in MC3T3-E1 cells, as evidenced by enhanced osteoblast adhesion, proliferation, and differentiation, as well as reduced apoptotic injury. In addition, the positive effects of CA were confirmed in vivo by enhanced osseointegration of TIs observed in mouse models of T2DM using microcomputed tomography and histological analyses. However, the pro-osteogenic effects of CA were almost completely nullified by the addition of LY294002. These findings demonstrated for the first time that CA administration ameliorates the impairment in osseointegration of TIs under conditions of T2DM via AKT/GSK3β/FYN pathway-mediated NRF2 activation. Given its antioxidative and pro-osteogenic properties, CA administration holds promise as a reliable therapeutic strategy in the future for implant restoration in patients with T2DM.