Abstract
This study was to explore the sequential signaling of disorganization of the actin cytoskeletal architecture by phloretin. RAW 264.7 macrophages were incubated with 1–20 μM phloretin for 5 days in the presence of RANKL. C57BL/6 mice were ovariectomized (OVX) and orally treated with 10 mg/kg phloretin once a day for 8 weeks. Phloretin allayed RANKL stimulated formation of actin podosomes with the concomitant retardation of the vinculin activation. Oral administration of phloretin suppressed the induction of femoral gelsolin and vinculin in OVX mice. The RANK-RANKL interaction resulted in the αvβ3 integrin induction, which was demoted by phloretin. The RANKL induction of actin rings and vacuolar-type H+-ATPase entailed Pyk2 phosphorylation and c-Src and c-Cbl induction, all of which were blunted by phloretin. Similar inhibition was also observed in phloretin-exposed OVX mouse femoral bone tissues with decreased trabecular collagen formation. Phloretin suppressed the paxillin induction in RANKL-activated osteoclasts and in OVX epiphyseal bone tissues. Also, phloretin attenuated the Syk phosphorylation and phospholipase Cγ induction by RANKL in osteoclasts. These results suggest that phloretin was an inhibitor of actin podosomes and sealing zone, disrupting αvβ3 integrin-c-Src-Pyk2/Syk signaling pathway for the regulation of actin cytoskeletal organization in osteoclasts.
Highlights
Large multinucleated osteoclasts specialized for bone resorption play a key role in bone turnover [1, 2]
Osteoclast differentiation is regulated by macrophage colony-stimulating factor and receptor activator of nuclear factor κB ligand (RANKL) interacting with their respective receptors of c-fms and RANK, on monocyte/macrophage precursors in vitro and in vivo [2, 5]
Based on the evidence that plant compounds such as green tea (−)-epigallocatechin gallate (EGCG) may block pathological bone loss and optimize bone health [23], this study investigated that phloretin (Figure 1(a)) antagonizing bone resorption allayed actin cytoskeletal reorganization into podosome belts in osteoclasts
Summary
Large multinucleated osteoclasts specialized for bone resorption play a key role in bone turnover [1, 2]. A relatively excessive activity of bone-resorptive osteoclasts often eventuates in the common bone disorder osteoporosis [3]. The magnitude of bone resorption of osteoclasts reflects their prevailing number and matrix-degrading capacity [4]. Understanding the means by which osteoclasts resorb bone conveys both physiological significance and clinical significance. Estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to postmenopausal osteoporosis characterized by low bone mass and microarchitectural deterioration of bone tissues [6]. First-line pharmacological therapies for postmenopausal osteoporosis include agents inhibiting bone resorption, thereby improving bone strength and reducing osteoporotic fracture [7,8,9]
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