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 Review of Fracture Healing and Outcomes Assessment

2020 ◽  
Vol 3 ◽  
Author(s):  
Adam Knoximprs ◽  
Anthony McGuire ◽  
Christopher Collier ◽  
Melissa Kacena ◽  
Roman Natoli
Keyword(s):  
Fracture Healing ◽  
Bone Fractures ◽  
Healing Process ◽  
Biomechanical Testing ◽  
Fracture Repair ◽  
Long Bone ◽  
Micro Computed Tomography ◽  
Fracture Callus ◽  
Medical Interventions ◽  
Healing Assessment

Background/Objective: Long bone fractures are of the most common and costly medical traumas humans experience.  Adequate characterization of the fracture healing process and development of potential medical interventions generally involves fracture induction operations on animal models of varying treatment or genetic groups, then analyzing relative repair success via synthesis of diverse assessment methodologies.  This review discusses the procedures, relevant parameters, special considerations, and key correlations of these major methodologies of fracture repair quantification.  Methods: A literature review was conducted for articles discussing the procedures or identifying correlations between each of the major fracture healing assessment methodologies.    Results: These methodologies include biomechanical testing, which provides the most direct quantification of skeletal functionality; micro-computed tomography, which enables high resolution visualization of fracture callus architecture; histology which helps elucidate the intricate processes underlying fracture repair; and x-ray which offers a non-invasive and clinically relevant view of fracture repair progress.  Each of these methodologies measure parameters directly correlating to restored functionality of fractured bone.  Conclusion: When appropriately integrated, synthesis of relevant parameters from each methodology of fracture repair assessment enables a comprehensive understanding of varying fracture healing outcomes and associated causalities.  Scientific/Clinical Policy Impact and Implications: This review may guide the interpretation and planning of fracture healing studies utilizing murine models. 

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 Osteoblast‐Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing

2015 ◽  
Vol 30 (9) ◽  
pp. 1572-1584 ◽  
Author(s):  
Tao Wang ◽  
Yongmei Wang ◽  
Alicia Menendez ◽  
Chak Fong ◽  
Muriel Babey ◽  
...  
Keyword(s):  
Bone Formation ◽  
Fracture Healing ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Specific Loss ◽  
Igf1r Signaling

scholarly journals The transcriptome of fracture healing defines mechanisms of coordination of skeletal and vascular development during endochondral bone formation

2011 ◽  
Vol 26 (11) ◽  
pp. 2597-2609 ◽  
Author(s):  
Rachel Grimes ◽  
Karl J Jepsen ◽  
Jennifer L Fitch ◽  
Thomas A Einhorn ◽  
Louis C Gerstenfeld
Keyword(s):  
Bone Formation ◽  
Fracture Healing ◽  
Vascular Development ◽  
Endochondral Bone Formation ◽  
Endochondral Bone

scholarly journals Endogenous Production of n-3 Polyunsaturated Fatty Acids Promotes Fracture Healing in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Yuhui Chen ◽  
He Cao ◽  
Dawei Sun ◽  
Changxin Lin ◽  
Liang Wang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Fracture Healing ◽  
Histological Analysis ◽  
Callus Formation ◽  
Healing Process ◽  
Proximal Femoral Fracture ◽  
Fracture Repair ◽  
Micro Ct ◽  
Micro Computed Tomography ◽  
X Ray

Bone fracture is a global healthcare issue for high rates of delayed healing and nonunions. Although n-3 polyunsaturated fatty acid (PUFA) is considered as a beneficial factor for bone metabolism, only few studies till date focused on the effects of n-3 PUFAs on fracture healing. In this study, we investigated the effect of endogenous n-3 PUFAs on fracture healing by measuring femur fracture repair in bothfat-1transgenic mice and WT mice. Proximal femoral fracture model was established infat-1transgenic mice and WT mice, respectively, and then the fracture was analyzed by using X-ray, micro-computed tomography (micro-CT), and histological assessment at 7, 14, 21, 28, and 35 days after fixation. The results showed that compared with WT mice,fat-1mice exhibited acceleration in fracture healing through radiographic and histological analysis (18–21 days versus 21–28 days postfracture). Meanwhile, X-ray and micro-CT analysis that showed better remodeling callus formation were in thefat-1group compared to WT group. Furthermore, histological analysis revealed that endogenous n-3 PUFAs promoted local endochondral ossification and accelerated the remodeling of calcified calluses after fracture. In conclusion, the present study indicated that endogenously produced n-3 PUFAs promote fracture healing process and accelerate bone remodeling in mice, and supplementation of n-3 PUFAs was positively associated with fracture healing.

scholarly journals Roles of Chondrocytes in Endochondral Bone Formation and Fracture Repair

2016 ◽  
Vol 96 (1) ◽  
pp. 23-30 ◽  
Author(s):  
R.J. Hinton ◽  
Y. Jing ◽  
J. Jing ◽  
J.Q. Feng
Keyword(s):  
Bone Formation ◽  
Fracture Repair ◽  
Endochondral Bone Formation ◽  
Endochondral Bone

scholarly journals Correlating mRUST scoring with fracture healing in the mouse model

2020 ◽  
Vol 3 ◽  
Author(s):  
Anthony McGuire ◽  
Adam Knox ◽  
Caio de Andrade Staut ◽  
Melissa Kacena ◽  
Roman Natoli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fracture Healing ◽  
Bone Fractures ◽  
Healing Process ◽  
Fracture Repair ◽  
Long Bone ◽  
Post Surgery ◽  
Method Of Assessment ◽  
Non Destructive

Background/Objective: Long bone fractures are an expensive and frequent cause of disability in humans. Research seeking to accelerate and improve the healing process is more essential than ever. Animal models, mice especially, provide an inexpensive and reproducible model of in vivo fracture healing. However, many measures of murine fracture healing outcomes are either expensive or destructive, limiting their ability to be translated to clinical studies. We seek to determine how these measures such as biomechanics, µCT, and histology correlate to the relatively new, inexpensive, and non-destructive method of mRUST scoring in a mouse model.  Methods: One hundred and thirty-five, 12-week old male C57BL6/J mice were divided into nine groups of 15 mice. Mice underwent a surgically created, femoral fracture. At biweekly timepoints, anteroposterior and lateral radiographs were taken, and 15 mice were sacrificed at each time point (7, 10, 14, 17, 21, 24, 28, 35, and 42 days post-surgery) for biomechanical, µCT, and histological analyses. The modified Radiographic Union Scale for Tibial fractures (mRUST scoring) provides a score based on the visualization of a callus and fracture line in four cortices on the radiographs. Data analysis will be performed to determine the degree of correlation between mRUST scoring and other fracture healing outcomes.  Results/Conclusion: Data collection in this experiment is still forthcoming. Upon successful completion of this project, we will have established numerical correlations between mRUST scoring and other fracture healing outcomes, such as biomechanics, µCT microarchitecture, and histology. These correlations will provide a powerful tool in future mouse fracture healing studies, as data on the state and strength of fracture repair could be determined by simple radiograph.  Scientific/Clinical Policy Impact and Implications: This study will both provide future murine fracture studies with an inexpensive and non-destructive method of assessment that is more directly translatable to human fracture studies. 

Identifying Candidate Mechanoregulators of Skeletal Development

2009 ◽  
Author(s):  
Niamh C. Nowlan ◽  
Patrick J. Prendergast ◽  
Shahragim Tajbakhsh ◽  
Paula Murphy
Keyword(s):  
Skeletal Muscle ◽  
Endochondral Ossification ◽  
Muscle Development ◽  
Skeletal Development ◽  
Endochondral Bone Formation ◽  
Mechanical Forces ◽  
Endochondral Bone ◽  
Mutant Strains ◽  
The Relationship

Studying the relationship between mechanical forces and skeletal development can provide vital clues to the mechanoregulation of skeletogenesis, providing important information to tissue engineers hoping to create functional cartilage or bone in vitro. Many studies of the mechanoregulation of skeletal development have focused on the chick embryo e.g., [1, 2]. However, as no endochondral ossification takes place in the embryonic chick long bones [1], mammalian systems must be used to examine the effect of mechanical forces on endochondral bone formation. Mouse mutant strains exist in which muscle development is affected, providing models with which to examine skeletogenesis in the absence of skeletal muscle contractions. One such strain is Pax3sp/sp [3], also known as splotch. The splotch mutant lacks the transcription factor Pax3, which prevents the migration of muscle pre-cursor cells into the limb buds, resulting in a complete absence of skeletal muscle.

scholarly journals Rapid expression of collagen type X gene of non-hypertrophic chondrocytes in the grafted chick periosteum demonstrated by in situ hybridization.

1993 ◽  
Vol 41 (5) ◽  
pp. 679-684 ◽  
Author(s):  
N Nagamoto ◽  
K Iyama ◽  
M Kitaoka ◽  
Y Ninomiya ◽  
H Yoshioka ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Endochondral Ossification ◽  
Collagen Type ◽  
Collagen Type I ◽  
Fracture Repair ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Type I ◽  
X Gene

We investigated the spatiotemporal localization of collagen Type I, II, and X mRNAs in the subcutaneously grafted chick periosteum by in situ hybridization. Five days after transplantation, we noted three types of histological findings in the grated tissue. (a) Developing trabecular bone exhibited proliferation of spindle-shaped fibroblastic cells and polygonal osteoblasts with moderate signals for collagen Type I mRNA. (b) Developing cartilage contained ovoid chondrocytes with a moderate level of both collagen Type I and II mRNAs. Differentiating chondrocytes with increased collagen Type X mRNA developed during the course of endochondral ossification. (c) An atypical mass of cartilage weakly stained with alcian blue was composed of a large number of non-hypertrophic chondrocytes exhibiting high signals for collagen Type X mRNA. At Day 9, we observed the typical histological features of both membranous and endochondral ossification. However, sparsely distributed chondrocytes with high signals for collagen Type X mRNA were also demonstrated in osteoid and/or woven bone. The phenotype of chondrocytes showing rapid expression of collagen Type X gene derived from grafted periosteum seems to participate in the important role of endochondral bone formation in the early stage of fracture repair.

scholarly journals Influence of high-frequency cyclical stimulation on the bone fracture-healing process: mathematical and experimental models

2011 ◽  
Vol 369 (1954) ◽  
pp. 4278-4294 ◽  
Author(s):  
María José Gómez-Benito ◽  
Libardo Andrés González-Torres ◽  
Esther Reina-Romo ◽  
Jorge Grasa ◽  
Belén Seral ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Healing ◽  
Mechanical Stimulation ◽  
Bone Fracture ◽  
High Frequency ◽  
Endochondral Ossification ◽  
Healing Process ◽  
Bone Fracture Healing ◽  
Bone Healing Process ◽  
Low Magnitude

Mechanical stimulation affects the evolution of healthy and fractured bone. However, the effect of applying cyclical mechanical stimuli on bone healing has not yet been fully clarified. The aim of the present study was to determine the influence of a high-frequency and low-magnitude cyclical displacement of the fractured fragments on the bone-healing process. This subject is studied experimentally and computationally for a sheep long bone. On the one hand, the mathematical computational study indicates that mechanical stimulation at high frequencies can stimulate and accelerate the process of chondrogenesis and endochondral ossification and consequently the bony union of the fracture. This is probably achieved by the interstitial fluid flow, which can move nutrients and waste from one place to another in the callus. This movement of fluid modifies the mechanical stimulus on the cells attached to the extracellular matrix. On the other hand, the experimental study was carried out using two sheep groups. In the first group, static fixators were implanted, while, in the second one, identical devices were used, but with an additional vibrator. This vibrator allowed a cyclic displacement with low magnitude and high frequency (LMHF) to be applied to the fractured zone every day; the frequency of stimulation was chosen from mechano-biological model predictions. Analysing the results obtained for the control and stimulated groups, we observed improvements in the bone-healing process in the stimulated group. Therefore, in this study, we show the potential of computer mechano-biological models to guide and define better mechanical conditions for experiments in order to improve bone fracture healing. In fact, both experimental and computational studies indicated improvements in the healing process in the LMHF mechanically stimulated fractures. In both studies, these improvements could be associated with the promotion of endochondral ossification and an increase in the rate of cell proliferation and tissue synthesis.

Sign in / Sign up

Export Citation Format

Share Document