Amelioration of bone fragility by pulsed electromagnetic fields in type 2 diabetic KK-Ay mice involving Wnt/β-catenin signaling

Abstract

Type 2 diabetes mellitus (T2DM) results in compromised bone microstructure and quality, and subsequently increased risks of fractures. However, it still lacks safe and effective approaches resisting T2DM bone fragility. Pulsed electromagnetic fields (PEMF) exposure has proven to be effective in accelerating fracture healing and attenuating osteopenia/osteoporosis induced by estrogen deficiency. Nevertheless, whether and how PEMF resist T2DM-associated bone deterioration remain not fully identified. The KK-Ay mouse was used as the T2DM model. We found that PEMF stimulation with 2 h/day for 8 weeks remarkably improved trabecular bone microarchitecture, decreased cortical bone porosity, and promoted trabecular and cortical bone material properties in KK-Ay mice. PEMF stimulated bone formation in KK-Ay mice, as evidenced by increased serum levels of bone formation (osteocalcin and P1NP), enhanced bone formation rate and increased osteoblast number. PEMF significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. PEMF exerted beneficial effects on osteoblast- and osteocyte-related gene expression in the skeleton of KK-Ay mice. Nevertheless, PEMF exerted no effect on serum biomarkers of bone resorption (TRAcP5b and CTX-1), osteoclast number or osteoclast-specific gene expression (TRAP and cathepsin K). PEMF upregulated gene expression of canonical Wnt ligands (including Wnt1, Wnt3a and Wnt10b), but not non-canonical Wnt5a. PEMF also upregulated skeletal protein expression of downstream p-GSK-3β and β-catenin in KK-Ay mice. Moreover, PEMF-induced improvement in bone microstructure, mechanical strength and bone formation in KK-Ay mice was abolished after intragastric administration with the Wnt antagonist ETC-159. Together, our results suggest that PEMF can improve bone microarchitecture and quality by enhancing the biological activities of osteoblasts and osteocytes, which are associated with the activation of the Wnt/β-catenin signaling pathway. PEMF might become an effective countermeasure against T2DM-induced bone deterioration.

Effects of diabetes on osteocytes

“…Several studies in rodent models of T2D, with compromised bone quality and strength, have reported effects of diabetes on osteocytes. For example, various types of physical activity (e.g., wheel running, swimming, pulsed electromagnetic field stimulation) represent stimuli that, as noted earlier, produce biomechanical loads and forces sensed by osteocytes; thus, exercise has been shown to act as an effective countermeasure to prevent or reverse T2D-related skeletal fragility [41,42,43 ▪ ]. Interestingly, in the study that used pulsed electromagnetic field stimulation, T2D-induced osteocyte apoptosis was alleviated and sclerostin levels were reduced suggesting that exercise maintains a healthy osteocyte lacuno-canalicular network in the context of T2D [43 ▪ ].…”

“…For example, various types of physical activity (e.g., wheel running, swimming, pulsed electromagnetic field stimulation) represent stimuli that, as noted earlier, produce biomechanical loads and forces sensed by osteocytes; thus, exercise has been shown to act as an effective countermeasure to prevent or reverse T2D-related skeletal fragility [41,42,43 ▪ ]. Interestingly, in the study that used pulsed electromagnetic field stimulation, T2D-induced osteocyte apoptosis was alleviated and sclerostin levels were reduced suggesting that exercise maintains a healthy osteocyte lacuno-canalicular network in the context of T2D [43 ▪ ]. Furthermore, given that increased circulating sclerostin levels have been consistently reported in human T2D patients [44–46], antisclerostin antibodies may mimic the effects of exercise by reversing T2D-related skeletal fragility as shown by a preclinical study in rats with T2D [47].…”

Challenges to Improve Bone Healing Under Diabetic Conditions

“…The application of PEMF treatment for patients with osteoporosis can significantly increase bone density and prevent bone loss ( 141 , 142 ). Studies on animal models of diabetes found that LIPEMF can restore the expression of Runx2 through the Wnt/β-catenin signaling pathway and reverse the deterioration of bone microstructure and strength, thereby preventing bone loss caused by diabetes, but has no effect on osteoclasts ( 143 – 145 ). The positive effect of LIPEMF in promoting bone healing has been confirmed in a large number of experiments.…”

The interdependent relationship between the nitric oxide signaling pathway and primary cilia in pulse electromagnetic field‐stimulated osteoblastic differentiation

“…1 The US Food and Drug Administration approved PEMFs as a safe and effective means for treating non-unions and osteoporosis based upon multicenter, randomized and prospective clinical studies in 1970s. [2][3][4] Additionally, results from experimental work have shown that in addition to improving bone quality and strength and promoting osteogenesis, [5][6][7][8] PEMFs also inhibit osteoclastic resorption with no stated side effects. 9 However, despite all these, the clinical promotion and application of PEMFs has not been as ideal as people had originally expected so far.…”