Estrogen receptor α- (ERα), but not ERβ-signaling, is crucially involved in mechanostimulation of bone fracture healing by whole-body vibration

Haffner‐Luntzer, Melanie; Kovtun, Anna; Lackner, Ina; Mödinger, Yvonne; Hacker, Steffen; Liedert, Astrid; Tuckermann, Jan; Ignatius, Anita

doi:10.1016/j.bone.2018.01.017

Cited by 30 publications

(37 citation statements)

References 58 publications

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“…Limitations of this animal model are that the total bone mineral density (BMD) loss is less than in human patients, that bone loss after OVX varies greatly between different mouse strains and that OVX does not completely mimic the kinetic and the underlying cause of natural menopause. During bone healing, OVX mice display delayed fracture bridging, callus maturation, disturbed immune response, and reduced angiogenesis as well as diminished mechano‐responsiveness similar to osteoporotic patients, demonstrating the translational relevance of this animal model. One drawback is that most fracture healing studies using OVX mice are conducted in a diaphyseal fracture setup .…”

Section: Comorbidities Influencing Fracture Healingmentioning

confidence: 93%

Review of Animal Models of Comorbidities in Fracture‐Healing Research

Haffner‐Luntzer¹,

Hankenson

Ignatius³

et al. 2019

Journal Orthopaedic Research

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There is clinical evidence that patient-specific comorbidities like osteoporosis, concomitant tissue injury, and ischemia may strongly interfere with bone regeneration. However, underlying mechanisms are still unclear. To study these mechanisms in detail, appropriate animal models are needed. For decades, bone healing has been studied in large animals, including dogs, rabbits, pigs, or sheep. However, large animal models display a limited ability to study molecular pathways and cellular functions. Therefore in recent years, mice and rats have become increasingly popular as a model organism for fracture healing research due to the availability of molecular analysis tools and transgenic models. Both large and small animals can be used to study comorbidities and risk factors, modelling the human clinical situation. However, attention has to be paid when choosing an appropriate model due to species differences between large animals, rodents, and humans. This review focuses on large and small animal models for the common comorbidities ischemic injury/reduced vascularization, osteoporosis, and polytrauma, and critically discusses the translational and molecular aspects of these models. Here, we review material which was presented at the workshop "Animal

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Section: Comorbidities Influencing Fracture Healingmentioning

confidence: 93%

Review of Animal Models of Comorbidities in Fracture‐Healing Research

Haffner‐Luntzer¹,

Hankenson

Ignatius³

et al. 2019

Journal Orthopaedic Research

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“…Our ndings showing that there is no statistically signi cant bene cial effect of estrogen treatment on callus formation, as established by BMD measured by pQCT, are in apparent contrast to observations with preclinical models. They show that estrogen administration, although at much higher doses however, strengthens indeed the properties of bones of ovariectomized animals after femoral fracture [4,8,9,[11][12][13][14]38]. However, there are no studies yet which determine the minimal dose of estrogen that causes a bene cial effect on bone healing in the preclinical model organisms without producing the known side effects of estrogen.…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that mechanostimulation by low-magnitude high frequency vibration was shown to provoke anabolic effects on the intact skeleton of both mice and human. This effect is estrogen-dependent and shown to be mediated primarily via the estrogen receptor alpha in mice, and vibration-induced effects on fracture healing in combination with estrogen treatment have also been shown to improve the osteopenic bone structure and increased the bone stiffness in preclinical studies [14,[39][40][41]. Thus, it is possible that such a combination of treatments rather than estrogen treatment alone could improve the healing of bone fractures by positively affecting callus BMD as measured by pQCT.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, estrogen treatment of mice with bone fractures led to enhanced healing, i.e. the chondrocyte areas were larger, callus mineralization was increased, and the neocortex was thicker when compared to untreated control animals [4,8,9,[11][12][13][14]. Furthermore, estrogen treatment also led to bene cial effects on the biomechanical properties of the bones [4].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of low-dose estrogen on callus BMD as measured by pQCT in postmenopausal women

Jäckle

Kolb

Schilling

et al. 2020

Preprint

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Background: Osteoporosis affects elderly patients of both sexes. It is characterized by an increased fracture risk due to defective remodeling of the bone microarchitecture. It affects in particular postmenopausal women due to their decreased levels of estrogen. Preclinical studies with animals demonstrated that loss of estrogen had a negative effect on bone healing and that increasing the estrogen level led to a better bone healing. We asked whether increasing the estrogen level in menopausal patients has a beneficial effect on bone mineral density (BMD) during callus formation after a bone fracture. Methods: To investigate whether estrogen has a beneficial effect on callus BMD of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13 years ± 11.99) were treated with estrogen and 45 patients (75.62 years ± 10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and six weeks after the surgery. Comparative measurements were performed at the fractured site and at the corresponding position of the non-fractured arm. Results: We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients . Conclusions: Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on callus BMD as measured by pQCT, as recently shown in preclinical animal models.

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“…Estrogen receptor (ER) is therefore proposed to play a critical role, as ER is also a signaling molecule in mechanotransduction. A few of ours and other recent studies successfully had validated the concept that ER‐α is crucially involved in vibration‐enhanced osteoporotic fracture healing and the effect was influenced by estrogen level . However, these studies rarely involved the evaluation of skeletal muscles and thus, the future research direction should focus on the interplay among sarcopenia, osteoporotic fracture healing, estrogen levels and vibration treatment in order to formulate effective treatment for the musculoskeletal system as a whole.…”

Section: Discussionmentioning

confidence: 99%

Impaired Fracture Healing in Sarco‐Osteoporotic Mice Can Be Rescued by Vibration Treatment Through Myostatin Suppression

Zhang

Chim

Wang

et al. 2019

Journal Orthopaedic Research

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Sarcopenia is highly prevalent in fragility fracture patients and is associated with delayed healing. In this study, we investigated the effect of low-magnitude high-frequency vibration (LMHFV) on osteoporotic fracture with sarcopenia and the potential role of myostatin. Osteoporotic fractures created in sarcopenic SAMP8, non-sarcopenic SAMR1 were randomized to control or LMHFV (SAMP8, SAMR1, SAMP8-V, or SAMR1-V) groups. Healing and myostatin expression were evaluated at 2, 4, and 6 weeks post-fracture. In vitro, conditioned-media were collected from myofibers isolated from aged and young SAMP8 or C2C12 myoblasts with or without LMHFV. Osteoblastic MC3T3-E1 under osteogenic differentiation were treated with plain or conditioned-medium (±myostatin propeptide). LMHFV significantly enhanced callus formation was in non-sarcopenic SAMR1 mice; but the enhancement effect was not significant in SAMP8 mice at week 2. Myostatin expressions in callus and biceps femoris of SAMP8 group were significantly higher all groups with significant negative correlation with callus size (R 2 = 0.7256; p = 0.0004). Mechanical properties (week 4) and callus remodeling (week 6) were inferior in SAMP8 versus SAMR1 and were significantly enhanced by LMHFV. Alkaline Phosphatase (ALP) and Runx2 expression of MC3T3-E1 was lower in aged myofiber compared with young, but upregulated by LMHFV or myostatin inhibition; also confirmed with C2C12. LMHFV enhanced early callus formation, microarchitecture, callus remodeling and mechanical properties of fracture healing in both SAMP8 and SAMR1; however, more effective in non-sarcopenic SAMR1 mice. Impaired fracture healing in sarcopenic SAMP8 mice is attributed by elevated myostatin expression in callus and muscle, which correlated negatively with callus formation.

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Estrogen receptor α- (ERα), but not ERβ-signaling, is crucially involved in mechanostimulation of bone fracture healing by whole-body vibration

Cited by 30 publications

References 58 publications

Review of Animal Models of Comorbidities in Fracture‐Healing Research

Review of Animal Models of Comorbidities in Fracture‐Healing Research

Analysis of low-dose estrogen on callus BMD as measured by pQCT in postmenopausal women

Impaired Fracture Healing in Sarco‐Osteoporotic Mice Can Be Rescued by Vibration Treatment Through Myostatin Suppression

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