scholarly journals YAP and TAZ promote periosteal osteoblast precursor expansion and differentiation for fracture repair

2020 ◽  
Author(s):  
Christopher D. Kegelman ◽  
Madhura P. Nijsure ◽  
Yasaman Moharrer ◽  
Hope B. Pearson ◽  
James H. Dawahare ◽  
...  
Keyword(s):  
Bone Formation ◽  
Fracture Healing ◽  
Bone Fracture ◽  
Callus Formation ◽  
Fracture Repair ◽  
Binding Motif ◽  
Adult Onset ◽  
Bone Fracture Healing ◽  
Fracture Callus ◽  
Endochondral Bone

ABSTRACTIn response to bone fracture, periosteal progenitor cells proliferate, expand, and differentiate to form cartilage and bone in the fracture callus. These cellular functions require the coordinated activation of multiple transcriptional programs, and the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) regulate osteochondroprogenitor activation during endochondral bone development. However, recent observations raise important distinctions between the signaling mechanisms used to control bone morphogenesis and repair. Here, we tested the hypothesis that YAP and TAZ regulate osteochondroprogenitor activation during endochondral bone fracture healing. Constitutive YAP and/or TAZ deletion from Osterix-expressing cells impaired both cartilage callus formation and subsequent mineralization. However, this could be explained either by direct defects in osteochondroprogenitor differentiation after fracture, or by developmental deficiencies in the progenitor cell pool prior to fracture. Consistent with the second possibility, we found that developmental YAP/TAZ deletion produced long bones with impaired periosteal thickness and cellularity. Therefore, to remove the contributions of developmental history, we next generated adult onset-inducible knockout mice (using Osx1-CretetOff) in which YAP and TAZ were deleted prior to fracture, but after normal development. Adult onset-induced YAP/TAZ deletion had no effect on cartilaginous callus formation, but impaired bone formation at 14 days post-fracture (dpf). Earlier, at 4 dpf, adult onset-induced YAP/TAZ deletion impaired the proliferation and expansion of osteoblast precursor cells located in the shoulder of the callus. Further, activated periosteal cells isolated from this region at 4 dpf exhibited impaired osteogenic differentiation in vitro upon YAP/TAZ deletion. Finally, confirming the effects on osteoblast function in vivo, adult onset-induced YAP/TAZ deletion impaired bone formation in the callus shoulder at 7 dpf, prior to the initiation of endochondral ossification. Together, these data show that YAP and TAZ promote the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing.

scholarly journals Histone demethylase LSD1 is critical for endochondral ossification during bone fracture healing

2020 ◽  
Vol 6 (45) ◽  
pp. eaaz1410
Author(s):  
Jun Sun ◽  
Heng Feng ◽  
Wenhui Xing ◽  
Yujiao Han ◽  
Jinlong Suo ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fracture Healing ◽  
Bone Regeneration ◽  
Bone Fracture ◽  
Endochondral Ossification ◽  
Callus Formation ◽  
Critical Factor ◽  
Fracture Repair ◽  
Retinoic Acid Signaling ◽  
Bone Fracture Healing

Bone fracture is repaired predominantly through endochondral ossification. However, the regulation of endochondral ossification by key factors during fracture healing remains largely enigmatic. Here, we identify histone modification enzyme LSD1 as a critical factor regulating endochondral ossification during bone regeneration. Loss of LSD1 in Prx1 lineage cells severely impaired bone fracture healing. Mechanistically, LSD1 tightly controls retinoic acid signaling through regulation of Aldh1a2 expression level. The increased retinoic acid signaling in LSD1-deficient mice suppressed SOX9 expression and impeded the cartilaginous callus formation during fracture repair. The discovery that LSD1 can regulate endochondral ossification during fracture healing will benefit the understanding of bone regeneration and have implications for regenerative medicine.

scholarly journals Pericytes as a Source of Osteogenic Cells in Bone Fracture Healing

2019 ◽  
Vol 20 (5) ◽  
pp. 1079 ◽  
Author(s):  
Sopak Supakul ◽  
Kenta Yao ◽  
Hiroki Ochi ◽  
Tomohito Shimada ◽  
Kyoko Hashimoto ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Fracture ◽  
Bone Fractures ◽  
Callus Formation ◽  
Bone Diseases ◽  
Lineage Tracing ◽  
Osteogenic Potential ◽  
Bone Fracture Healing ◽  
Osteogenic Cells

Pericytes are mesenchymal cells that surround the endothelial cells of small vessels in various organs. These cells express several markers, such as NG2, CD146, and PDGFRβ, and play an important role in the stabilization and maturation of blood vessels. It was also recently revealed that like mesenchymal stem cells (MSCs), pericytes possess multilineage differentiation capacity, especially myogenic, adipogenic, and fibrogenic differentiation capacities. Although some previous studies have reported that pericytes also have osteogenic potential, the osteogenesis of pericytes can still be further elucidated. In the present study, we established novel methods for isolating and culturing primary murine pericytes. An immortalized pericyte line was also established. Multilineage induction of the pericyte line induced osteogenesis, adipogenesis, and chondrogenesis of the cells in vitro. In addition, pericytes that were injected into the fracture site of a bone fracture mouse model contributed to callus formation. Furthermore, in vivo pericyte-lineage-tracing studies demonstrated that endogenous pericytes also differentiate into osteoblasts and osteocytes and contribute to bone fracture healing as a cellular source of osteogenic cells. Pericytes can be a promising therapeutic candidate for treating bone fractures with a delayed union or nonunion as well as bone diseases causing bone defects.

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

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
K. Jäckle ◽  
J. P. Kolb ◽  
A. F. Schilling ◽  
C. Schlickewei ◽  
M. Amling ◽  
...  
Keyword(s):  
Bone Density ◽  
Beneficial Effect ◽  
Fracture Healing ◽  
Postmenopausal Women ◽  
Bone Healing ◽  
Bone Fracture ◽  
Low Dose ◽  
Callus Formation ◽  
Trial Registration ◽  
Bone Fracture Healing

Abstract 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 6 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. Trial registration Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858. Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858.

scholarly journals Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling

2019 ◽  
Vol 116 (17) ◽  
pp. 8615-8622 ◽  
Author(s):  
Melanie Haffner-Luntzer ◽  
Sandra Foertsch ◽  
Verena Fischer ◽  
Katja Prystaz ◽  
Miriam Tschaffon ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Fracture Healing ◽  
Bone Fracture ◽  
Psychosocial Stress ◽  
Modern Society ◽  
Bone Fracture Healing ◽  
Fracture Callus ◽  
Chronic Psychosocial Stress ◽  
Late Stages

Chronic psychosocial stress/trauma represents an increasing burden in our modern society and a risk factor for the development of mental disorders, including posttraumatic stress disorder (PTSD). PTSD, in turn, is highly comorbid with a plethora of inflammatory disorders and has been associated with increased bone fracture risk. Since a balanced inflammatory response after fracture is crucial for successful bone healing, we hypothesize that stress/trauma alters the inflammatory response after fracture and, consequently, compromises fracture healing. Here we show, employing the chronic subordinate colony housing (CSC) paradigm as a clinically relevant mouse model for PTSD, that mice subjected to CSC displayed increased numbers of neutrophils in the early fracture hematoma, whereas T lymphocytes and markers for cartilage-to-bone transition and angiogenesis were reduced. At late stages of fracture healing, CSC mice were characterized by decreased bending stiffness and bony bridging of the fracture callus. Strikingly, a single systemic administration of the β-adrenoreceptor (AR) blocker propranolol before femur osteotomy prevented bone marrow mobilization of neutrophils and invasion of neutrophils into the fracture hematoma, both seen in the early phase after fracture, as well as a compromised fracture healing in CSC mice. We conclude that chronic psychosocial stress leads to an imbalanced immune response after fracture via β-AR signaling, accompanied by disturbed fracture healing. These findings offer possibilities for clinical translation in patients suffering from PTSD and fracture.

scholarly journals Exogenous PTH 1-34 Attenuates Impaired Fracture Healing in Endogenous PTH Deficiency Mice via Activating Indian Hedgehog Signaling Pathway and Accelerating Endochondral Ossification

2022 ◽  
Vol 9 ◽  
Author(s):  
Cheng Ma ◽  
Huan Liu ◽  
Yifan Wei ◽  
He Li ◽  
Dengshun Miao ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Signaling Pathway ◽  
Endochondral Ossification ◽  
Healing Process ◽  
Fracture Repair ◽  
Luciferase Reporter ◽  
Endochondral Bone Formation ◽  
Fracture Callus ◽  
Endochondral Bone ◽  
Bony Callus

Fracture healing is a complicated, long-term, and multistage repair process. Intermittent administration of parathyroid hormone (PTH) has been proven effective on intramembranous and endochondral bone formation during the fracture healing process, however, the mechanism is unclear. In this study, we investigated the role of exogenous PTH and endogenous PTH deficiency in bone fracture healing and explored the mechanism by using PTH knockout (PTH-/-) mice and ATDC5 cells. In a mouse femur fracture model, endogenous PTH deficiency could delay endochondral ossification whereas exogenous PTH promotes accumulation of endochondral bone, accelerates cartilaginous callus conversion to bony callus, enhances maturity of bony callus, and attenuates impaired fracture healing resulting from endogenous PTH deficiency. In fracture callus tissue, endogenous PTH deficiency could inhibit chondrocyte proliferation and differentiation whereas exogenous PTH could activate the IHH signaling pathway to accelerate endochondral ossification and rescue impaired fracture healing resulting from endogenous PTH deficiency. In vitro, exogenous PTH promotes cell proliferation by activating IHH signaling pathway on ATDC5 cells. In mechanistic studies, by using ChIP and luciferase reporter assays, we showed that PTH could phosphorylate CREB, and subsequently bind to the promoter of IHH, causing the activation of IHH gene expression. Therefore, results from this study support the concept that exogenous PTH 1-34 attenuates impaired fracture healing in endogenous PTH deficiency mice via activating the IHH pathway and accelerating endochondral ossification. Hence, the investigation of the mechanism underlying the effects of PTH treatment on fracture repair might guide the exploration of effective therapeutic targets for fracture.

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

2020 ◽  
Author(s):  
Katharina Blanka Dr. Jäckle ◽  
Jan Philipp Kolb ◽  
Arndt F Schilling ◽  
Carsten Schlickewei ◽  
Michael Amling ◽  
...  
Keyword(s):  
Bone Density ◽  
Beneficial Effect ◽  
Fracture Healing ◽  
Postmenopausal Women ◽  
Bone Healing ◽  
Bone Fracture ◽  
Low Dose ◽  
Callus Formation ◽  
Trial Registration ◽  
Bone Fracture Healing

Abstract 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.Trial registration: Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858. Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858.

scholarly journals PHOSPHO1 is essential for normal bone fracture healing

2018 ◽  
Vol 7 (6) ◽  
pp. 397-405 ◽  
Author(s):  
M. W. Morcos ◽  
H. Al-Jallad ◽  
J. Li ◽  
C. Farquharson ◽  
J. L. Millán ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Fracture ◽  
Healing Process ◽  
Bone Volume ◽  
Fracture Repair ◽  
Bending Test ◽  
Bone Fracture Healing ◽  
Trabecular Thickness ◽  
Three Point Bending ◽  
Normal Bone

Objectives Bone fracture healing is regulated by a series of complex physicochemical and biochemical processes. One of these processes is bone mineralization, which is vital for normal bone development. Phosphatase, orphan 1 (PHOSPHO1), a skeletal tissue-specific phosphatase, has been shown to be involved in the mineralization of the extracellular matrix and to maintain the structural integrity of bone. In this study, we examined how PHOSPHO1 deficiency might affect the healing and quality of fracture callus in mice. Methods Tibial fractures were created and then stabilized in control wild-type (WT) and Phospho1-/- mice (n = 16 for each group; mixed gender, each group carrying equal number of male and female mice) at eight weeks of age. Fractures were allowed to heal for four weeks and then the mice were euthanized and their tibias analyzed using radiographs, micro-CT (μCT), histology, histomorphometry and three-point bending tests. Results The μCT and radiographic analyses revealed a mild reduction of bone volume in Phospho1-/- callus, although it was not statistically significant. An increase in trabecular number and a decrease in trabecular thickness and separation were observed in Phospho1-/- callus in comparison with the WT callus. Histomorphometric analyses showed that there was a marked increase of osteoid volume over bone volume in the Phospho1-/- callus. The three-point bending test showed that Phospho1-/- fractured bone had more of an elastic characteristic than the WT bone. Conclusion Our work suggests that PHOSPHO1 plays an integral role during bone fracture repair and may be a therapeutic target to improve the fracture healing process. Cite this article: M. W. Morcos, H. Al-Jallad, J. Li, C. Farquharson, J. L. Millán, R. C. Hamdy, M. Murshed. PHOSPHO1 is essential for normal bone fracture healing: An Animal Study. Bone Joint Res 2018;7:397–405. DOI: 10.1302/2046-3758.76.BJR-2017-0140.R2.

scholarly journals The mechanosensitive Piezo1 orchestrating angiogenesis is essential in bone fracture repair

2019 ◽  
Author(s):  
Peng Chen ◽  
Gangyu Zhang ◽  
Shan Jiang ◽  
Yile Ning ◽  
Bo Deng ◽  
...  
Keyword(s):  
Bone Formation ◽  
Fracture Healing ◽  
Bone Fracture ◽  
Wide Distribution ◽  
Fracture Repair ◽  
Biological Processes ◽  
High Importance ◽  
Clinical Strategies ◽  
Underlying Mechanisms ◽  
Osteoblast Maturation

AbstractMechanical ion channel protein Piezo1 play vital roles in angiogenesis which has been proved to be high importance in varieties of biological processes. Bone formation in the fracture repair requires oxygen and nutrients from new blood vessels generated from fractured lesion. Understanding the underlying mechanisms linking angiogenesis and bone formation must be of great value for improved fracture healing. Here we employed mice with genetically modified endothelial specific depletion of Piezo1 channels to explore the hypothesis that Piezo1 is vital to the initiation of fracture healing. In this study, we demonstrated that Piezo1 expression and wide distribution along the bone and impaired endothelial Piezo1 channels result in derangements in bone fracture repair. Intriguingly, the calcium activated proteolytic caplain activity severely disrupted during vascularization, precluded osteoblast maturation and mineralization and subsequently the phosphorylated PI3K-AKT reduction. Furthermore, Piezo1 endothelial disruption impaired Notch signaling in bone union. These data collectively suggest that Piezo1 channels serve as a basis for clinical strategies to improve bone regeneration and treat delayed or nonunion in bone fracture.

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