Mechanical Vibration Mitigates the Decrease of Bone Quantity and Bone Quality of Leptin Receptor-Deficient Db/Db Mice by Promoting Bone Formation and Inhibiting Bone Resorption

Abstract

Leptin, a major hormonal product of adipocytes, is involved in regulating appetite and energy metabolism. Substantial studies have revealed the anabolic actions of leptin on skeletons and bone cells both in vivo and in vitro. Growing evidence has substantiated that leptin receptor-deficient db/db mice exhibit decreased bone mass and impaired bone microstructure despite several conflicting results previously reported. We herein systematically investigated bone microarchitecture, mechanical strength, bone turnover and its potential molecular mechanisms in db/db mice. More importantly, we also explored an effective approach for increasing bone mass in leptin receptor-deficient animals in an easy and noninvasive manner. Our results show that deterioration of trabecular and cortical bone microarchitecture and decreases of skeletal mechanical strength-including maximum load, yield load, stiffness, energy, tissue-level modulus and hardness-in db/db mice were significantly ameliorated by 12-week, whole-body vibration (WBV) with 0.5 g, 45 Hz via micro-computed tomography (mCT), three-point bending, and nanoindentation examinations. Serum biochemical analysis shows that WBV significantly decreased serum tartrate-resistant acid phosphatase 5b (TRACP5b) and CTx-1 levels and also mitigated the reduction of serum osteocalcin (OCN) in db/db mice. Bone histomorphometric analysis confirmed that decreased bone formation-lower mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone-in db/db mice were suppressed by WBV. Real-time PCR assays show that WBV mitigated the reductions of tibial alkaline phosphatase (ALP), OCN, Runt-related transcription factor 2 (RUNX2), type I collagen (COL1), BMP2, Wnt3a, Lrp6, and b-catenin mRNA expression, and prevented the increases of tibial sclerostin (SOST), RANK, RANKL, RANL/osteoprotegerin (OPG) gene levels in db/db mice. Our results show that WBV promoted bone quantity and quality in db/db mice with obvious anabolic and anticatabolic effects. This study not only enriches our basic knowledge about bone quality and bone turnover mechanisms in leptin receptordeficient animals, but also advances our understanding of the skeletal sensitivity of leptin-resistant db/db mice in response to external mechanical stimulation.

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

“…Leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice have bone- and bone compartment-specific alterations in bone microarchitecture, reduced bone length, mass and density, and reduced bone quality (Jing, et al 2016; Williams, et al 2011). The growth plates of ob/ob mice are abnormal due, in part, to poorly organized collagen fibril arrangement (Kishida, et al 2005).…”

“…However, bone resorption is reduced, implicating impaired osteoclast activity. The osteoclast defect in these mice contributes to growth plate abnormalities and development of mild osteopetrosis: the pathological retention of calcified cartilage into adulthood in bone in ob/ob and db/db mice likely contributes to the reduced bone quality noted in these animals (Jing et al 2016). …”

Association between Casual Serum Triglyceride Levels and Bone Resorption Activity in Japanese Middle-aged and Elderly Women

“…Bone state is closely related to the balance between bone formation and bone resorption. Accelerated bone resorption can lead to bone fragility and an increased risk of fracture due to loss of bone mineral density BMD and deterioration of bone quality 24 . Based on the results of the present study, we propose the hypothesis that reduced bone resorption activity may contribute, in part, to reduced fracture risk in Japanese middle-aged and elderly female patients with hypertriglyceridemia, and that acceleration of bone resorption may be linked to bone fragility and an increased risk of fractures in patients with lower plasma TG.…”

Differential skeletal response in adult and aged rats to independent and combinatorial stimulation with pulsed electromagnetic fields and mechanical vibration

“…Animals in the WBV group were stimulated with daily WBV loading (0.5 g , 45 Hz) with 1 hour/day for 8 weeks. This WBV loading protocol has also been proved effective for increasing bone mass and strength in osteoporotic animals . Rats in the PEMF + WBV group were subjected to 2 hours/day PEMF exposure followed by 1 hour/day WBV stimulation for 8 weeks.…”

“…Bone is a highly mechanosensitive and adaptive system, and increased physiological loads on the skeleton via aerobic or anaerobic exercise can lead to anabolic bone changes and improved bone status . In particular, a large body of experimental evidence over the two decades has substantiated that whole‐body vibration (WBV) with low intensity (<1 g ) and high frequency (≥30 Hz) improves bone quantity and/or quality in both normal and osteoporotic animals induced with ovariectomy, disuse, or diabetes by triggering anabolic and anti‐catabolic bone responses . WBV has also been found to increase bone mineral density (BMD) in young and postmenopausal women, revealing the potential of WBV serving as a surrogate for strenuous physical exercise.…”