The Role of Muscle in Bone Repair: The Cells, Signals, and Tissue Responses to Injury

Shah, Krupa; Majeed, Zahraa; Jonason, Jennifer H.; O’Keefe, Regis J.

doi:10.1007/s11914-013-0146-3

Cited by 45 publications

(33 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The simplicity of this model compared with a closed or open fracture model (eg, smaller and more confined callus formation, lack of gait defect) supports a direct role for muscle/bone crosstalk in fracture healing [12,19,21,28]. Previous studies using closed and open fracture models have reported conflicting findings over the potential benefit (or lack thereof) of muscle paralysis on fracture healing [3,13].…”

Section: Discussionmentioning

confidence: 73%

Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation

Ausk

Gross

Bain

2015

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

Background Short-term muscle atrophy induced by botulinum toxin A (BTxA) has been observed to impair osteogenesis in a rat closed femur fracture model. However, it is unclear whether the underlying mechanism is a direct effect of BTxA on muscle-bone interactions or an indirect effect that is driven by skeletal unloading. Because skeletal trauma in the closed fracture model also leads to disuse atrophy, we sought to mitigate this confounding variable by examining BTxA effects on muscle-bone interactions in two complementary in vivo models in which osteogenesis is induced in the absence of skeletal unloading. The overall aim of this study was to identify a potential strategy to inhibit pathological bone formation and heterotopic ossification (HO). Questions/purposes (1) Does muscle paralysis inhibit periosteal osteogenesis induced by a transcortical defect? (2) Does muscle paralysis inhibit heterotopic bone formation stimulated by intramuscular bone morphogenetic protein (BMP) injection? Methods Focal osteogenesis was induced in the right hindlimb of mice through surgical initiation of a small transcortical defect in the tibia (fracture callus; n = 7/group) or intramuscular injection of BMP-2 (HO lesion; n = 6/group), both in the presence/absence of adjacent calf paralysis. High-resolution micro-CT images were obtained in all experimental groups 21 days postinduction and total volume (ie, perimeter of periosteal callus or HO lesion) and bone volume (calcified tissue within the total volume) were quantified as primary outcome measures. Finally, these outcome measures were compared to determine the effect of muscle paralysis on inhibition of local osteogenesis in both studies.Results After a transcortical defect, BTxA-treated mice showed profound inhibition of osteogenesis in the periosteal fracture callus 21 days postsurgery compared with saline-treated mice (total volume: 0.08 ± 0.06 versus 0.42 ± 0.11 mm 3 , p \ 0.001; bone volume: 0.07 ± 0.05 versus 0.32 ± 0.07 mm 3 , p \ 0.001). Similarly, BMP-2-induced HO formation was inhibited by adjacent muscle paralysis at the same time point (total volume: 1.42 ± 0.31 versus 3.42 ± 2.11 mm 3 , p = 0.034; bone volume: 0.68 ± 0.18 versus 1.36 ± 0.79 mm 3 , p = 0.045). Conclusions Our data indicate that BTxA-induced neuromuscular inhibition mitigated osteogenesis associated with both a transcortical defect and BMP-2-induced HO. Clinical Relevance Focal neuromuscular inhibition represents a promising new approach that may lead to a new clinical intervention to mitigate trauma-induced HO, a healthcare challenge that is severely debilitating for civilian and war-wounded populations, is costly to both the patient and the healthcare system, and currently lacks effective treatments.

show abstract

Section: Discussionmentioning

confidence: 73%

Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation

Ausk

Gross

Bain

2015

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

show abstract

“…Also, there is increasing evidence that skeletal muscle may participate in bone fracture repair. 15 It has recently been reported that skeletal muscle is able to produce a unique type of stem cells which can differentiate into osteoblasts. 15 If muscle at fracture sites could also be effectively infected by AAV-DJ-COX2 vector, the COX2 products generated from the transduced muscle could act on other types of cells participating in fracture repair.…”

Section: Discussionmentioning

confidence: 99%

“…15 It has recently been reported that skeletal muscle is able to produce a unique type of stem cells which can differentiate into osteoblasts. 15 If muscle at fracture sites could also be effectively infected by AAV-DJ-COX2 vector, the COX2 products generated from the transduced muscle could act on other types of cells participating in fracture repair. In fact, the myofibers with slow turnover may provide COX2 products in a sustained period of time compared to the rapidly proliferating cells at fracture site.…”

Section: Discussionmentioning

confidence: 99%

Local administration of AAV-DJ pseudoserotype expressing COX2 provided early onset of transgene expression and promoted bone fracture healing in mice

et al. 2015

View full text Add to dashboard Cite

We have previously obtained compelling proof-of-principle evidence for COX2 gene therapy for fracture repair using integrating retroviral vectors. For this therapy to be suitable for patient uses, a suitable vector with high safety profile must be used. Accordingly, this study sought to evaluate the feasibility of AAV as the vector for this COX2 gene therapy, because AAV raises less safety issues than the retroviral vectors used previously. However, an appropriate AAV serotype is required to provide early increase in and adequate level of COX2 expression that is needed for fracture repair. Herein, we reported that AAV-DJ, an artificial AAV pseudoserotype, is highly effective in delivering COX2 gene to fracture sites in a mouse femoral fracture model. Compared with AAV-2, the use of AAV-DJ led to ~5-fold increase in infectivity in mesenchymal stem cells (MSCs) and provided an earlier and significantly higher level of transgene expression at the fracture site. Injection of this vector at a dose of 7.5 × 10(11) genomic copies led to high COX2 level at the fracture site on day 3 after injections and significantly promoted fracture union at 21 days, as analyzed by radiography and μ-CT. The therapeutic effect appears to involve enhanced osteoblastic differentiation of MSCs and remodeling of callus tissues to laminar bone. This interpretation is supported by the enhanced expression of several key genes participating in the fracture repair process. In conclusion, AAV-DJ is a promising serotype for the AAV-based COX2 gene therapy of fracture repair in humans.

show abstract

“…The teeth supporting alveolar bone is characterized by distinctive features such as the continuous and rapid remodeling in response to mechanical force stimuli [21] lack of muscle stem cells, which plays a critical role in fracture healing [22,23], healing without histological cartilage formation [24] as well as potential infection of healing alveolar bone due to constant oral microbial challenge surrounding the alveolar bone [25]. Therefore, the characterization of an alveolar bone healing model is important to provide specific insight on alveolar bone healing with different type of BRMs.…”

Section: British Biomedical Bulletin Issn 2347-5447mentioning

confidence: 99%