Mice with a heterozygous Lrp6 deletion have impaired fracture healing

Burgers, Travis; Vivanco, Juan; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, Joshua; Williams, Bart O.

doi:10.1038/boneres.2016.25

Cited by 11 publications

(5 citation statements)

References 49 publications

(61 reference statements)

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“…Two images were averaged per frame (Bouxsein et al, 2010). Following scanning, the binarized images were used to calculate several three-dimensional bone healing parameters as detailed previously (Burgers et al, 2016, Komatsu et al., 2010). In brief, tissue volume (TV) generated by NRecon delineates tissue from non-tissue, which we defined as the callus volume.…”

Section: Methodsmentioning

confidence: 99%

Forces associated with launch into space do not impact bone fracture healing

Childress

Brinker

Gong

et al. 2018

Life Sciences in Space Research

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Segmental bone defects (SBDs) secondary to trauma invariably result in a prolonged recovery with an extended period of limited weight bearing on the affected limb. Soldiers sustaining blast injuries and civilians sustaining high energy trauma typify such a clinical scenario. These patients frequently sustain composite injuries with SBDs in concert with extensive soft tissue damage. For soft tissue injury resolution and skeletal reconstruction a patient may experience limited weight bearing for upwards of 6 months. Many small animal investigations have evaluated interventions for SBDs. While providing foundational information regarding the treatment of bone defects, these models do not simulate limited weight bearing conditions after injury. For example, mice ambulate immediately following anesthetic recovery, and in most cases are normally ambulating within 1-3 days post-surgery. Thus, investigations that combine disuse with bone healing may better test novel bone healing strategies. To remove weight bearing, we have designed a SBD rodent healing study in microgravity (µG) on the International Space Station (ISS) for the Rodent Research-4 (RR-4) Mission, which launched February 19, 2017 on SpaceX CRS-10 (Commercial Resupply Services). In preparation for this mission, we conducted an end-to-end mission simulation consisting of surgical infliction of SBD followed by launch simulation and hindlimb unloading (HLU) studies. In brief, a 2 mm defect was created in the femur of 10 week-old C57BL6/J male mice (n = 9-10/group). Three days after surgery, 6 groups of mice were treated as follows: 1) Vivarium Control (maintained continuously in standard cages); 2) Launch Negative Control (placed in the same spaceflight-like hardware as the Launch Positive Control group but were not subjected to launch simulation conditions); 3) Launch Positive Control (placed in spaceflight-like hardware and also subjected to vibration followed by centrifugation); 4) Launch Positive Experimental (identical to Launch Positive Control group, but placed in qualified spaceflight hardware); 5) Hindlimb Unloaded (HLU, were subjected to HLU immediately after launch simulation tests to simulate unloading in spaceflight); and 6) HLU Control (single housed in identical HLU cages but not suspended). Mice were euthanized 28 days after launch simulation and bone healing was examined via micro-Computed Tomography (µCT). These studies demonstrated that the mice post-surgery can tolerate launch conditions. Additionally, forces and vibrations associated with launch did not impact bone healing (p = .3). However, HLU resulted in a 52.5% reduction in total callus volume compared to HLU Controls (p = .0003). Taken together, these findings suggest that mice having a femoral SBD surgery tolerated the vibration and hypergravity associated with launch, and that launch simulation itself did not impact bone healing, but that the prolonged lack of weight bearing associated with HLU did impair bone healing. Based on these findings, we proceeded with testing the efficacy ...

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Section: Methodsmentioning

confidence: 99%

Forces associated with launch into space do not impact bone fracture healing

Childress

Brinker

Gong

et al. 2018

Life Sciences in Space Research

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“…Animal studies, in which the β-catenin signaling was either inhibited or activated in chondrocytes, osteoblasts, or osteocytes, demonstrated that activation of β-catenin signaling promotes osteoblast differentiation and bone formation and inhibition of osteoclast formation and bone resorption. [1][2][3][4][5][6][7] However, the detailed mechanisms of how postnatal bone growth and bone remodeling are regulated by β-catenin signaling remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation

Shu

Zhao

et al. 2020

Bone Res

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Axin1 is a negative regulator of β-catenin signaling and its role in osteoblast precursor cells remains undefined. In the present studies, we determined changes in postnatal bone growth by deletion of Axin1 in osteoblast precursor cells and analyzed bone growth in newborn and postnatal Axin1 Osx mice and found that hypertrophic cartilage area was largely expanded in Axin1 Osx KO mice. A larger number of chondrocytes and unabsorbed cartilage matrix were found in the bone marrow cavity of Axin1 Osx KO mice. Osteoclast formation in metaphyseal and subchondral bone areas was significantly decreased, demonstrated by decreased TRAPpositive cell numbers, associated with reduction of MMP9-and cathepsin K-positive cell numbers in Axin1 Osx KO mice. OPG expression and the ratio of Opg to Rankl were significantly increased in osteoblasts of Axin1 Osx KO mice. Osteoclast formation in primary bone marrow derived microphage (BMM) cells was significantly decreased when BMM cells were cultured with conditioned media (CM) collected from osteoblasts derived from Axin1 Osx mice compared with BMM cells cultured with CM derived from WT mice. Thus, the loss of Axin1 in osteoblast precursor cells caused increased OPG and the decrease in osteoclast formation, leading to delayed bone growth in postnatal Axin1 Osx KO mice.

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“…For example, LRP5 À/À mice, LRP6 À/+ mice and mice overexpressing the LRP5/6-antagonist Kremen2 showed reduced bone formation and mechanical stability of the fracture callus. (12,13) By contrast, mice lacking Wnt inhibitors such as sclerostin and midkine or overexpressing Wnt agonists such as Wnt7b displayed accelerated fracture healing. (14)(15)(16)(17) Wnt3 has been extensively studied as a therapeutic option and might be a promising candidate.…”

Section: Introductionmentioning

confidence: 99%

Wnt1 Boosts Fracture Healing by Enhancing Bone Formation in the Fracture Callus

Haffner‐Luntzer¹,

Ragipoglu²,

Ahmad³

et al. 2020

Journal of Bone and Mineral Research

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Despite considerable improvement in fracture care, 5%-10% of all fractures still heal poorly or result in nonunion formation. Therefore, there is an urgent need to identify new molecules that can be used to improve bone fracture healing. One activator of the Wnt-signaling cascade, Wnt1, has recently gained attention for its intense osteoanabolic effect on the intact skeleton. The aim of the present study was to investigate whether Wnt1 might be a promising molecule to accelerate fracture healing both in skeletally healthy and osteoporotic mice that display a diminished healing capacity. Transgenic mice for a temporary induction of Wnt1 specifically in osteoblasts (Wnt1-tg) were subjected to femur osteotomy. Non-ovariectomized and ovariectomized Wnt1-tg mice displayed significantly accelerated fracture healing based on a strong increase in bone formation in the fracture callus. Transcriptome profiling revealed that Hippo/yes1-associated transcriptional regulator (YAP)-signaling and bone morphogenetic protein (BMP) signaling pathways were highly enriched in the fracture callus of Wnt1-tg animals. Immunohistochemical staining confirmed increased activation of YAP1 and expression of BMP2 in osteoblasts in the fracture callus. Therefore, our data indicate that Wnt1 boosts bone formation during fracture healing via YAP/BMP signaling both under healthy and osteoporotic conditions. To further test a potential translational application of Wnt1, we applied recombinant Wnt1 embedded into a collagen gel during critical-size bone-defect repair. Mice treated with Wnt1 displayed increased bone regeneration compared to control mice accompanied by increased YAP1/BMP2 expression in the defect area. These findings are of high clinical relevance because they indicate that Wnt1 could be used as a new therapeutic agent to treat orthopedic complications in the clinic.

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Mice with a heterozygous Lrp6 deletion have impaired fracture healing

Cited by 11 publications

References 49 publications

Forces associated with launch into space do not impact bone fracture healing

Forces associated with launch into space do not impact bone fracture healing

Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation

Wnt1 Boosts Fracture Healing by Enhancing Bone Formation in the Fracture Callus

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