Overview of Biological Mechanisms and Applications of Three Murine Models of Bone Repair: Closed Fracture with Intramedullary Fixation, Distraction Osteogenesis, and Marrow Ablation by Reaming

Abstract

Fractures are one of the most common large-organ, traumatic injuries in humans, and osteoporosis-related fractures are the fastest growing health care problem of aging. Elective orthopedic surgeries of the bones and joints also represent some of most common forms of elective surgeries performed. Optimal repair of skeletal tissues is necessary for successful outcomes of these many different orthopedic surgical treatments. Research focused on post-natal skeletal repair is therefore of immense clinical importance and of particular relevance in situations in which bone tissue healing is compromised due to the extent of tissue trauma or specific medical co-morbidities. Three commonly used murine surgical models of bone healing, closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming are presented. The biological aspects of these models are contrasted and the types of research questions that may be addressed with these models are presented.

Earliest phases of chondrogenesis are dependent upon angiogenesis during ectopic bone formation in mice

“…Comparing patterns of gene expression between DBM induced ectopic bone formation on the periosteal surface to that seen after fracture suggests that no intramembranous bone formation or osteoprogenitor recruitment takes place in this ectopic bone formation model. This conclusion is based both on the lack of the induction of any genes associated with osteoblast matrix during POD 2–7 and the much sharper and very discreet temporal phases of expression of genes associated with cartilage and bone cells that were seen in this model in comparison to fracture [10,34]. Fracture and osteotomy models also induce both an extensive inflammatory response, as well as a marrow response both of which will affect angiogenesis.…”

Mouse Models of Bone Healing: Fracture, Marrow Ablation, and Distraction Osteogenesis

“…Complete regain of bone structure, histology, and function and mRNA expression back to the pre-fracture state takes 42 to 63 days. See the companion paper to this one (Bragdon et al, 2015) for a complete description of the biological processes associated with fracture healing.…”

“…Marrow ablation (Basic Protocol 3) is strictly an endosteal model of intramembranous bone formation that is little influenced by mechanical signals, since the cortical bone remains intact. Each protocol offers unique advantages for studying different aspects of postnatal bone repair and regeneration as outlined below, as well as in the companion review (Bragdon et al, 2015). NOTE: All protocols using live animals must first be reviewed and approved by an Institutional Animal Care and Use Committee (IACUC) or must conform to governmental regulations regarding the care and use of laboratory animals.…”

Systemically administered MSCs given 24hrs after osteotomy do not affect bone formation in rat distraction osteogenesis

“…As widely used as this technique has become, the protracted time periods for the distraction and consolidation phases limit its clinical utility. [1,3,[7][8][9][10] Strategies to speed up either of these two phases would decrease treatment time and improve patient quality of life.…”

“…Furthermore, it may be advantageous to introduce stem cells the day after surgery at a time point when natural chemokine gradients are forming and the inflammatory cascade is at its peak. [8,9,26] During this time, migration and recruitment of regenerative cells is very high. 5 Mesenchymal stem cells (MSCs) have been found to migrate to fracture or drill hole sites demonstrating a positive osteogenic effect.…”