Elcatonin prevents bone loss caused by skeletal unloading by inhibiting preosteoclast fusion through the unloading-induced high expression of calcitonin receptors in bone marrow cells

Tsukamoto, Manabu; Menuki, Kunitaka; Murai, Teppei; Hatakeyama, Akihisa; Takada, Shinichiro; Furukawa, Kayoko; Sakai, Akinori

doi:10.1016/j.bone.2016.01.025

Cited by 15 publications

(9 citation statements)

References 49 publications

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“…The length of the femur represented the distance between the top of the greater trochanter to the distal end of the lateral femoral condyle. We also measured the BMD (mg/cm 2 ) in the right femur using dualenergy X-ray absorption (DXA; DCS-600; Aloka, Tokyo, Japan) [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted with Trizol reagents (Invitrogen) from the skin of mice or Dermal fibroblasts isolated from the skin of mice sacrificed for the day-3 wound healing model after careful removal of blood cells, using the sham-operated skin as controls. All procedures were performed as described previously [ 19 , 22 , 24 – 25 , 28 , 30 – 31 ]. RNase-free conditions were used to prevent mRNA degradation.…”

Section: Methodsmentioning

confidence: 99%

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Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-deficient mice

et al. 2018

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BackgroundWe have reported that WNT10A plays a critical role in the growth of fibroblasts/myofibroblasts and microvascular endothelial cells, i.e.; wound healing/scarring. To ascertain the in vivo regulatory, central functions of WNT10A, we examined the net effects of WNT10A depletion using WNT10A-deficient mice (WNT10A–/–).Methods and resultsWe generated WNT10A–/–mice, displaying a range of unique phenotypes of morpho/organogenetic failure, such as growth retardation, alopecia, kyphosis and infertility, and then focused on the functions of WNT10A in wound healing. We subjected C57BL/6J wild-type (WT) or WNT10A–/–mice to skin ulcer formation. The WNT10A–/–mice had significantly larger injured areas and delayed wound healing, which were associated with (a) a smaller number of fibroblasts/myofibroblasts and microvessels; and (b) more reduced expression and synthesis of collagen, compared with WT mice with intact WNT10A expression, especially in those with activated myofibroblasts.ConclusionsThese observations indicate that WNT10A signaling can play a pivotal in vivo role in wound healing by regulating the expression and synthesis of collagen, as one of fibrogenic factors, at least in part, and critical in vivo roles of WNT10A-mediated effective wound healing are extremely closely associated with collagen expression.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-deficient mice

et al. 2018

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“…To investigate the reason why bone formation in the KO mice was not promoted by the CE, we focused on the expression levels of osteogenic mRNAs and key cell cycle molecules based on our previous reports [ 10 , 25 , 27 ]. We detected a decrease in p21 mRNA expression in the bone marrow cells using quantitative RT-PCR after CE.…”

Section: Discussionmentioning

confidence: 99%

“…On the 10th experimental day, CFU-f colonies were fixed with fixation solution and treated with a substrate tablet for ALP (BCIP-NBT solution kit for ALP stain, nuclease tested; Nacalai Tesque, Kyoto, Japan) dissolved in ddw at 37 °C. Colonies comprising 50 cells were defined as CFU-f. We counted the total and ALP + CFU-f colonies with the culture dishes backlit at a fivefold magnification [ 16 , 19 – 25 ].…”

Section: Methodsmentioning

confidence: 99%

“…β-Actin served as an internal control. The amplification conditions were an initial 3 min at 95 °C and 40–50 cycles of denaturation at 95 °C for 30 s, annealing at each temperature for 30 s, and extension at 72 °C for 30 s. The mRNA expression levels were normalized to β-actin mRNA expression and expressed as relative values (fold change) compared to the expression levels in the WTGC group [ 10 , 14 , 25 – 27 ].…”

Section: Methodsmentioning

confidence: 99%

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Disruption of the Aldehyde Dehydrogenase 2 Gene Results in No Increase in Trabecular Bone Mass Due to Skeletal Loading in Association with Impaired Cell Cycle Regulation Through p21 Expression in the Bone Marrow Cells of Mice

et al. 2017

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Approximately 45% of people of East Asian descent have the inactive aldehyde dehydrogenase 2 (ALDH2) phenotype. The enzyme defect of ALDH2 has been found to adversely influence the risk of osteoporosis. The aim of this study was to clarify the effect of skeletal loading on trabecular bone structure and dynamics in Aldh2-disrupted mice in the absence of alcohol consumption. Four-week-old male Aldh2−/− (KO) and Aldh2+/+ (WT) mice were divided into a ground control (GC) group and a climbing exercise (CE) group in each genotype. The trabecular bone mineral density of the distal femur measured by peripheral quantitative computed tomography in the wild-type CE (WTCE) group was significantly higher than that in the wild-type GC (WTGC) group; however, there was no significant difference between the knockout CE (KOCE) and knockout GC (KOGC) groups. Bone histomorphometry revealed that osteogenic parameters were significantly increased in the WTCE group compared with the WTGC group, but not increased in the KOCE group compared with the KOGC group. Quantitative reverse transcriptase polymerase chain reaction and flow cytometry revealed that mRNA and protein expression levels of p21 were significantly decreased in the WTCE group compared with those in the WTGC group, while these differences were not observed between the KOGC and KOCE groups. This study provides the first in vivo evidence that p21 expression in the bone marrow is not decreased after skeletal loading and osteoblast differentiation is impaired in the absence of Aldh2 gene.

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Suppression of Bone Resorption by miR-141 in Aged Rhesus Monkeys

Yang

Zhang

Cai

et al. 2018

Journal of Bone and Mineral Research

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Aging-related osteoporosis (OP) is considered a serious public health concern. Approximately 30% of postmenopausal women suffer from OP; more than 40% of them risk fragility fractures. Multiple drugs have been prescribed to treat OP, but they are not ideal because of low cure rates and adverse side effects. miRNA-based gene therapy is a rapidly developing strategy in disease treatment that presents certain advantages, such as large-scale production capability, genetic safety, and rapid effects. miRNA drugs have been used primarily in cancer treatments; they have not yet been reported as candidates for osteoclast-targeted-OP treatment in primates. Their therapeutic efficacy has been limited by several shortcomings, such as low efficiency of selective delivery, insufficient expression levels in targeting cells, and unexpected side effects. Here, we identify miR-141 as a critical suppressor of osteoclastogenesis and bone resorption. The expression levels of miR-141 are positively correlated with BMD and negatively correlated with the aging of bones in both aged rhesus monkeys (Macaca mulatta) and osteoporotic patients. Selective delivery of miR-141 into the osteoclasts of aged rhesus monkeys via a nucleic acid delivery system allowed for a gradual increase in bone mass without significant effects on the health and function of primary organs. Furthermore, we found that the functional mechanism of miR-141 resides in its targeting of two osteoclast differentiation players, Calcr (calcitonin receptors) and EphA2 (ephrin type-A receptor 2 precursor). Our study suggests that miRNAs, such as miR-141, could play a crucial role in suppressing bone resorption in primates and provide reliable experimental evidence for the clinical application of miRNA in OP treatment. © 2018 American Society for Bone and Mineral Research.

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Elcatonin prevents bone loss caused by skeletal unloading by inhibiting preosteoclast fusion through the unloading-induced high expression of calcitonin receptors in bone marrow cells

Cited by 15 publications

References 49 publications

Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-deficient mice

Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-deficient mice

Disruption of the Aldehyde Dehydrogenase 2 Gene Results in No Increase in Trabecular Bone Mass Due to Skeletal Loading in Association with Impaired Cell Cycle Regulation Through p21 Expression in the Bone Marrow Cells of Mice

Suppression of Bone Resorption by miR-141 in Aged Rhesus Monkeys

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