A Radiographic and Histologic Study of Fracture Healing in Osteopetrotic Rats

Schmidt, Christopher J.; Marks, Sandy C.; Jordan, Christopher; Hawes, Lloyd E.

doi:10.1148/122.2.517

Cited by 7 publications

(4 citation statements)

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“…We found that Ccr2-/-osteoclasts had reduced bone resorption capacity compared with wild-type cells. Similar findings have been reported by Binder et al (Binder et al, 2009), who showed that Ccr2 mutant mice are osteopetrotic owing to the decreased function and number of osteoclasts in bone (Binder et al, 2009 (Marks and Schmidt, 1978;Schmidt et al, 1977), supporting our conclusion that defective osteoclasts lead to a delay in callus remodeling in Ccr2-null mice. These data indicate that the CCR2 signaling axis is required for adequate osteoclast function.…”

Section: Ccr2 Regulates Osteoclast Activitysupporting

confidence: 92%

Multiple roles for CCR2 during fracture healing

Xing

et al. 2010

Disease Models &Amp; Mechanisms

167

170

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SUMMARYBone injury induces an inflammatory response that involves neutrophils, macrophages and other inflammatory cells. The recruitment of inflammatory cells to sites of injury occurs in response to specific signaling pathways. The CC chemokine receptor type 2 (CCR2) is crucial for recruiting macrophages, as well as regulating osteoclast function. In this study, we examined fracture healing in Ccr2-/-mice. We first demonstrated that the expression of Ccr2 transcripts and the filtration of macrophages into fracture calluses were most robust during the early phases of fracture healing. We then determined that the number of macrophages at the fracture site was significantly lower in Ccr2-/-mice compared with wild-type controls at 3 days after injury. As a result, impaired vascularization, decreased formation of callus, and delayed maturation of cartilage were observed at 7 days after injury in mutant mice. At day 14, Ccr2-/-mice had less bone in their calluses. At day 21, Ccr2-/-mice had larger calluses and more bone compared with wild-type mice, suggesting a delayed remodeling. In addition, we examined the effect of Ccr2 mutation on osteoclasts. We found that a lack of Ccr2 did not affect the number of osteoclasts within fracture calluses at 21 days after injury. However, Ccr2-/-osteoclasts exhibited a decreased ability to resorb bone compared with wild-type cells, which could contribute to the delayed remodeling of fracture calluses observed in Ccr2-/-mice. Collectively, these results indicate that a deficiency of Ccr2 reduces the infiltration of macrophages and impairs the function of osteoclasts, leading to delayed fracture healing.

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Section: Ccr2 Regulates Osteoclast Activitysupporting

confidence: 92%

Multiple roles for CCR2 during fracture healing

Xing

et al. 2010

Disease Models &Amp; Mechanisms

167

170

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“…This hypothesis is supported by the observation that genetic or pharmacologic blockade of osteoclast activity in rodents enhances callus size. (42–45) Despite this size similarity, a major difference between these models and mice, however, is that callus structural and mechanical properties of rodents with impaired osteoclast function are increased, whereas these parameters are decreased in calluses. These observations strongly suggest that the bone laid down by Nf1 −/− osteoblasts has defective intrinsic properties leading to reduced callus mechanical strength in addition to increased callus size.…”

Section: Discussionmentioning

confidence: 99%

Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts

Wang

Nyman

Moss

et al. 2010

Journal of Bone and Mineral Research

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Postfracture tibial nonunion (pseudoarthrosis) leads to lifelong disability in patients with neurofibromatosis type I (NF1), a disorder caused by mutations in the NF1 gene. To determine the contribution of NF1 in bone healing, we assessed bone healing in the conditional mouse model lacking Nf1 specifically in osteoblasts. A closed distal tibia fracture protocol and a longitudinal study design were used. During the 21- to 28-day postfracture period, callus volume, as expected, decreased in wild-type but not in mice, suggesting delayed healing. At these two time points, bone volume (BV/TV) and volumetric bone mineral density (vBMD) measured by 3D micro–computed tomography were decreased in callus-bridging cortices and trabecular compartments compared with wild-type controls. Histomorphometric analyses revealed the presence of cartilaginous remnants, a high amount of osteoid, and increased osteoclast surfaces in calluses 21 days after fracture, which was accompanied by increased expression of osteopontin, Rankl, and Tgfβ. Callus strength measured by three-point bending 28 days after fracture was reduced in versus wild-type calluses. Importantly, from a clinical point of view, this defect of callus maturation and strength could be ameliorated by local delivery of low-dose lovastatin microparticles, which successfully decreased osteoid volume and cartilaginous remnant number and increased callus BV/TV and strength in mutant mice. These results thus indicate that the dysfunctions caused by loss of Nf1 in osteoblasts impair callus maturation and weaken callus mechanical properties and suggest that local delivery of low-dose lovastatin may improve bone healing in NF1 patients. © 2010 American Society for Bone and Mineral Research.

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“…Current models of fracture repair distinguish the early “nonspecific” anabolic and catabolic responses associated with normal wound repair and late “bone‐specific” responses mediated by osteoblasts and osteoclasts 17. Although fracture repair has been examined in ia/ia rats previously, these authors failed to examine closely the initial nonspecific anabolic responses and cartilage tissue removal and focused mainly on hard callus remodeling 9, 18. Our data support the concept that osteoclast function is not essential for nonmineralized cartilage removal during the early stages of endochondral fracture healing.…”

Section: Discussionmentioning

confidence: 99%

“…Two studies from the 1970s reported aberrant bone healing in ia/ia rat pups (fractured at 11–17 days). Compared to normal littermates, the ia/ia pups showed greater net callus mineralization and delayed hard callus remodeling 9. This phenotype could be rescued by transplantation of normal spleen cells 10.…”

mentioning

confidence: 96%

Characterization of the bone phenotype and fracture repair in osteopetrotic Incisors absent rats

McDonald

Morse

Peacock

et al. 2010

Journal Orthopaedic Research

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Osteopetrotic patients possess a genetic condition that leads to a deficiency in osteoclast number or function. Patients have a high bone density and suffer from an increased risk of fracture. The lack of normal osteoclast activity has the potential to impede repair by complicating orthopedic fixation and/or by affecting the biology of fracture healing. The naturally occurring incisors absent (ia/ia) rat was adopted as a rodent model of congenital osteopetrosis. A detailed phenotypic analysis of the ia/ia rat indicated that some functional recovery occurred between 7 and 9 weeks. Consequently a fracture repair study was undertaken using 5-week-old rats. Closed femoral fractures were generated in ia/ia rats and control ia/þ and þ/þ rats using an Einhorn apparatus. Fracture healing was examined radiologically and histologically at 1-3 weeks. No difference was seen in bridging between ia/ia and control rats at any time point. The ia/ia rats showed no delay in cartilage removal but showed a significant delay in hard callus remodeling. This is consistent with an essential role for osteoclasts in only the latter stages of endochondral bone repair. This delay in hard callus remodeling was offset by an increase in moment of inertia. ß

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A Radiographic and Histologic Study of Fracture Healing in Osteopetrotic Rats

Cited by 7 publications

References 0 publications

Multiple roles for CCR2 during fracture healing

Multiple roles for CCR2 during fracture healing

Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts

Characterization of the bone phenotype and fracture repair in osteopetrotic Incisors absent rats

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