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 Knockdown of SERPINB2 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the Wnt/β-catenin signalling pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kai Hang ◽  
Li Ying ◽  
Jinwu Bai ◽  
Yibo Wang ◽  
Zhihui Kuang ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Osteogenic Differentiation ◽  
Bone Fracture ◽  
Osteoblast Differentiation ◽  
Tibial Fracture ◽  
Bone Fractures ◽  
Bone Fracture Healing ◽  
Non Union

Abstract Background Globally, bone fractures are the most common musculoskeletal trauma, and approximately 8–10% of cases that fall into the categories of delayed or non-union healing. To date, there are no efficient pharmacological agents to accelerate the healing of bone fractures. Thus, it is necessary to find new strategies that accelerate bone healing and reduce the incidence of non-union or delayed fracture healing. Previous studies have revealed that the plasminogen activation system has been demonstrated to play an important role in bone metabolism. However, the function of SERPINB2 in the osteogenesis of hBMSCs remains unclear. Therefore, in this study, we investigated the effects and mechanism of SERPINB2 on osteogenic differentiation. Methods We investigated the osteogenesis effects of hBMSCs by both exogenous SerpinB2 protein and SERPINB2 gene silencing in vitro. Cell proliferation assay was used to assess the effect of exogenous SerpinB2 or SERPINB2 silencing on proliferation of hBMSCs. qPCR and Western blotting analysis detected the expression of target genes and proteins respectively. ALP staining was used to evaluated ALP activity and Alizarin Red staining (ARS) was used to evaluate mineral deposition. In vivo, a murie tibial fracture model was established, histological evaluation and radiographic analysis was used to confirm the therapeutic effects of SERPINB2 silencing in fracture healing. Statistical significance between two groups was determined by Student’s t test, one-way ANOVA or Bonferroni’s post-hoc test according to the distribution of the tested population. Results The addition of exogenous SerpinB2 protein inhibted osteoblast differentiation of hBMSCs in vitro, while SERPINB2 gene silencing significant promote osteoblast differentiation of hBMSCs in vitro. And silenced SERPINB2 gene also increased mineral deposits. Moreover, β-catenin levels were up-regulated by SERPINB2 gene depletion. And the enhancement of osteogenic differentiation induced by SERPINB2 silencing was almost inhibited by specific Wnt/β-catenin signaling pathway inhibitor. In a murine tibial fracture model, local injection of SERPINB2 siRNA improved bone fracture healing. Conclusions Taken together, these findings indicate that SERPINB2 silencing promoted osteogenic differentiation of BMSCs via the Wnt/β-catenin signaling pathway, and silenced SERPINB2 in vivo effectively promotes fracture healing, suggesting that SERPINB2 may be a novel target for bone fracture healing.

scholarly journals Knockdown of SERPINB2 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the Wnt/β-catenin signalling pathway

2021 ◽  
Author(s):  
Kai Hang ◽  
Li Ying ◽  
Jinwu Bai ◽  
Yibo Wang ◽  
Zhihui Kuang ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Osteogenic Differentiation ◽  
Bone Fracture ◽  
Osteoblast Differentiation ◽  
Tibial Fracture ◽  
Bone Fractures ◽  
Bone Fracture Healing ◽  
Non Union

Abstract Background Globally, bone fractures are the most common musculoskeletal trauma, and approximately 8–10% of cases that fall into the categories of delayed or non-union healing. Treatment of impaired healing in these patients not only represents a tremendous burden on healthcare systems but also increases patients’ pain and financial burdens. To date, there are no efficient pharmacological agents to accelerate the healing of bone fractures. Thus, it is necessary to find new strategies that accelerate bone healing and reduce the incidence of non-union or delayed fracture healing. Previous studies have revealed that the plasminogen activation system has been demonstrated to play an important role in bone metabolism. However, the function of SERPINB2 in the osteogenesis of hBMSCs remains unclear. Therefore, in this study, we investigated the effects and mechanism of Apelin on osteogenic differentiation. Methods We investigated the osteogenesis effects of hBMSCs by both exogenous SERPINB2 protein and SERPINB2 silencing in vitro. Cell proliferation assay was used to assess the effect of exogenous SERPINB2 or SERPINB2 silencing on proliferation of hBMSCs. qPCR and Western blotting analysis detected the expression of target genes and proteins respectively. ALP staining was used to evaluated ALP activity and Alizarin Red staining (ARS) was used to evaluate mineral deposition. In vivo, a murie tibial fracture model was established, histological evaluation and radiographic analysis was used to confirm the therapeutic effects of SERPINB2 silencing in fracture healing. statistical significance between two groups was determined by Student’s t test, one-way ANOVA or Bonferroni’s post-hoc test according to the distribution of the tested population.Results The addition of exogenous SERPINB2 protein inhibted osteoblast differentiation of hBMSCs in vitro, while SERPINB2 gene silencing significant promote osteoblast differentiation of hBMSCs in vitro. And silence SERPINB2 gene also increased mineral deposits. Moreover, β-catenin levels were up-regulated by SERPINB2 gene depletion. And the enhancement of osteogenic differentiation induced by SERPINB2 silencing was almost inhibited by specific Wnt/β-catenin signaling pathway inhibitors. In a murine tibial fracture model, local injection of SERPINB2 siRNA improved bone fracture healing. Conclusions Taken together, these findings indicate that SERPINB2 silencing promoted osteogenic differentiation of BMSCs via the Wnt/β-catenin signaling pathway, and silenced SERPINB2 in vivo effectively promotes fracture healing, suggesting that SERPINB2 may be a novel target for bone fracture healing.

scholarly journals Amygdalin Promotes Fracture Healing through TGF-β/Smad Signaling in Mesenchymal Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Jun Ying ◽  
Qinwen Ge ◽  
Songfeng Hu ◽  
Cheng Luo ◽  
Fengyi Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Fracture Healing ◽  
Bone Fracture ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Conditional Knockout ◽  
Mesenchymal Progenitor Cells ◽  
Bone Fracture Healing ◽  
Smad Signaling

Chondrogenesis and subsequent osteogenesis of mesenchymal stem cells (MSCs) and angiogenesis at injured sites are crucial for bone fracture healing. Amygdalin, a cyanogenic glycoside compound derived from bitter apricot kernel, has been reported to inhibit IL-1β-induced chondrocyte degeneration and to stimulate blood circulation, suggesting a promising role of amygdalin in fracture healing. In this study, tibial fractures in C57BL/6 mice were treated with amygdalin. Fracture calluses were then harvested and subjected to radiographic, histological, and biomechanical testing, as well as angiography and gene expression analyses to evaluate fracture healing. The results showed that amygdalin treatment promoted bone fracture healing. Further experiments using MSC-specific transforming growth factor- (TGF-) β receptor 2 conditional knockout (KO) mice (Tgfbr2Gli1-Cre) and C3H10 T1/2 murine mesenchymal progenitor cells showed that this effect was mediated through TGF-β/Smad signaling. We conclude that amygdalin could be used as an alternative treatment for bone fractures.

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 Numerical modelling of the ultrasound effect on bone fracture healing

2016 ◽  
Author(s):  
Κωνσταντίνος Γρίβας
Keyword(s):  
Numerical Modelling ◽  
Fracture Healing ◽  
Bone Fracture ◽  
Bone Fracture Healing ◽  
Ultrasound Effect

Η πώρωση οστικών καταγμάτων είναι μια εξαιρετικά σύνθετη διεργασία κατά τη διάρκεια της οποίας ποικίλοι κυτταρικοί και μοριακοί μηχανισμοί λαμβάνουν χώρα. Σκοπό της διδακτορικής διατριβής αποτέλεσε η δημιουργία ενός νέου πρότυπου υπολογιστικού εργαλείου το οποίο θα προσομοιώνει τη διαφοροποίηση των ιστών μετά από κάταγμα και θα διερευνεί την επίδραση των χαμηλής έντασης υπερήχων στη διαδικασία πώρωσης οστικών καταγμάτων, παρέχοντας εις βάθος καινούργια γνώση αναφορικά με τους ακριβείς μηχανισμούς που οδηγούν στην επιτάχυνση της ανάπλασης των καταγματικών οστών. Η παρούσα διδακτορική διατριβή υλοποιήθηκε σε τρεις φάσεις. Κατά τη διάρκεια της πρώτης φάσης αναπτύχθηκε μια νέα και απλή Μέθοδος Τοπικών Ολοκληρωτικών Εξισώσεων χωρίς Διακριτοποίηση (ΜΤΟχΔ) για την επίλυση του γραμμικού και μη-γραμμικού προβλήματος του πολλαπλασιασμού των μεσεγχυματικών κυττάρων με στόχο τη διερεύνηση της πιο αντιπροσωπευτικής από τις δύο περίπτωσης. Ακολούθως κατά τη διάρκεια της δεύτερης φάσης εργασιών υλοποιήθηκε ένα υβριδικό βιολογικό μαθηματικό μοντέλο βασισμένο σε αυτό της Peiffer et al. (2011). Το μοντέλο αυτό αποτελείται από α) ένα σύστημα Μερικών Διαφορικών Εξισώσεων (ΜΔΕ) που περιγράφει τη χωροχρονική εξέλιξη κυττάρων, αυξητικών παραγόντων, ιστών και της ακουστικής πίεσης του υπερήχου και β) ένα σύστημα εξισώσεων ταχύτητας για τα ενδοθηλιακά κύτταρα που ακτινογραφεί την ανάπτυξη του δικτύου των αιμοφόρων αγγείων. Η επίδραση των υπερήχων στο πολυεπίπεδο βιολογικό μοντέλο ελήφθη υπ’ όψιν με τέτοιο τρόπο ώστε πρωτίστως να επηρεάζει τη μεταφορά του Αγγειακού Ενδοθηλιακού Αυξητικού Παράγοντα (ΑΕΑΠ) σύμφωνα με προηγούμενες in vitro μελέτες. Τέλος, η τρίτη φάση της διδακτορικής διατριβής αφορά την παρουσίαση ενός μικρομηχανοβιολογικού μοντέλου βασισμένου στην μελέτη των Lacroix και Prendergast (2002) και εμπλουτισμένου με τους όρους που εισάγουν την επίδραση του υπερήχου στην πώρωση του οστού. Σε αυτή την κατεύθυνση συμπεριλαμβάνεται μια επαναληπτική διαδικασία η οποία συνδυάζει ένα μηχανικό μοντέλο που επιλύει το ποροελαστικό πρόβλημα και λαμβάνει υπ’ όψιν την επίδραση του μηχανικού φορτίου στον χρόνο, ένα βιολογικό μοντέλο διάχυσης για τον πολλαπλασιασμό των μεσεγχυματικών κυττάρων και το υβριδικό βιολογικό μοντέλο που αναπτύχθηκε κατά τη διάρκεια της δεύτερης φάσης. Οι καινοτόμες πτυχές της διδακτορικής διατριβής είναι α) η ανάπτυξη ενός νέου αριθμητικού μοντέλου το οποίο για πρώτη φορά προσομοιώνει τη διαδικασία της οστεοποίησης υπό την επίδραση των υπερήχων και β) η ανάπτυξη μια νέας και απλής ΜΤΟχΔ για την προσομοίωση του πολλαπλασιασμού των μεσεγχυματικών κυττάρων. Για το λόγο αυτό μπορεί να θεωρηθεί ως ένα βήμα προς την αξιολόγηση του υπερήχου στην διαδικασία πώρωσης καταγματικών οστών. Η εκτέλεση πειραματικών εφαρμογών υπερήχου σε συνδυασμό με την ανάπτυξη ενός πιο ολοκληρωμένου θεωρητικού πλαισίου μπορεί να βοηθήσει στην περαιτέρω κατανόηση του φαινομένου

Using the Doppler Effect to Measure the Vibration of Human Bones: In Vitro Studies

1994 ◽  
Vol 208 (2) ◽  
pp. 127-129 ◽  
Author(s):  
T Flint ◽  
L Nokes ◽  
M Maheson ◽  
J P Woodcock
Keyword(s):  
Fracture Healing ◽  
Bone Fracture ◽  
Doppler Effect ◽  
Bone Fracture Healing ◽  
Human Bones ◽  
Experimental Apparatus ◽  
In Vitro Assessment ◽  
The Doppler Effect

A novel application of ultrasound Doppler theory to the measurement of bone vibration is described. The theory and experimental apparatus is outlined and its initial calibration and in vitro assessment reported. It is speculated that this method may be used clinically in order to monitor in vivo 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 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 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.

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