Age- and genotype-dependence of bone material properties in the osteogenesis imperfecta murine model (oim).

Cortical mineralization of long bones was studied in collagen alpha2(I)-deficient mice (oim) used as a model for human osteogenesis imperfecta. Aspects of the age development of the mice were characterized by combining nanometer- to micrometer-scale structural analysis with microhardness measurements. Bone structure was determined from homozygous (oim/oim) and heterozygous (oim/+) mice and their normal (+/+) littermates as a function of animal age by small-angle X-ray scattering (SAXS) and quantitative backscattered electron imaging (qBEI) measurements. SAXS studies found anomalies in the size and arrangement of bone mineral crystals in both homozygous and heterozygous mice aged 1-14 months. Generally, the crystals were smaller in thickness and less well aligned in these mice compared with control animals. An increase in the mean crystal thickness of the bone was found within all three genotypes up to an age of 3 months. Vicker's hardness measurements were significantly enhanced for oim bone (homozygotes and heterozygotes) compared with controls. The microhardness values were correlated directly with increased mineral content of homozygous and heterozygous compared with control bone, as determined by qBEI analysis. There was also a significant increase of mineral content with age. Two possibilities for collagen-mineral association are discussed for explaining the increased hardness and mineral content of oim/oim bone, together with its decreased toughness and thinner mineral crystals. As a consequence of the present measurements, one model for oim bone could incorporate small and densely packed mineral crystals. A second model for possible collagen-mineral association in oim material would consist of two families of mineral crystals, one being smaller and the other being much larger than the crystals found in normal mouse long bones.     

Consequences of an osteogenesis imperfecta diagnosis for survival and ambulation

In osteogenesis imperfecta, time of initial fracture and radiographic appearance of long bones and ribs at time of initial fracture provide good prognostic indicators concerning survival and ambulation. Osteogenesis imperfecta congenita (OIC) comprises those patients with intrauterine and/or birth fractures. Radiographs of newborns with OIC-A show short, broad, and crumpled femurs and ribs, whereas initial radiographs of patients with OIC-B demonstrate bones with normal contours in spite of fractures. Osteogenesis imperfecta tarda (OIT) comprises those patients who fracture initially after birth. Patients with OIT-A fracture initially before walking begins, and patients with OIT-B after walking has begun. In OIC-A, 15 of 16 (94%) died; one survived but was wheelchair bound. In OIC-B, only two of 27 (8%) died, with 59% in wheelchairs and 33% ambulatory. No patients with OIT died. In OIT-A, 33% were in wheelchairs and 67% were ambulatory. In OIT-B, 100% were ambulatory.     

Increased susceptibility to microdamage in Brtl/+ mouse model for osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic disease of collagen or collagen-related proteins that adversely impacts bone mass and fracture resistance. Little is known regarding the role that microdamage plays in OI and whether or not OI bone is more prone to damage accumulation than bone with unaffected collagen. The Brtl/+ mouse is a heterozygous model for OI which contains a Gly349Cys substitution in one COL1A1 allele, and demonstrates a low ductility phenotype. At 8 weeks of age, Brtl/+ demonstrates an increase in osteoclast number, which mimics the upregulated bone turnover often found in OI patients. We hypothesize that upregulated osteoclast activity in Brtl/+ is due, in part, to increased remodeling associated with microdamage repair. In the present study, we used Brtl/+ to investigate the susceptibility of OI bone to microdamage. The mouse ulnar loading model was used to induce microdamage and to test the hypothesis that Brtl/+ is more susceptible to damage accumulation than age-matched wild type (WT) counterparts. Linear elastic fracture mechanics (LEFM) was used to investigate the fracture toughness properties of both Brtl/+ and WT bones to determine if there is any correlation with toughness and the degree of microdamage. Results show that Brtl/+ ulnae subject to normal cage activity demonstrate an inherently larger amount of microdamage than WT controls. Following axial compressive loading, Brtl/+ ulnae are more prone to damage than WT counterparts despite demonstrating a greater resistance to whole-bone deformation. Fracture toughness results demonstrate that Brtl/+ specimens, despite not exhibiting a significant difference, display a trend toward lower fracture toughness values than their WT counterparts. Correlations show that microdamage levels tend to increase as fracture toughness decreases. Together, these findings may have strong clinical implications for explaining increased fragility and remodeling activity in OI patients.     

Rotatory atlanto-axial dislocation in an infant with osteogenesis imperfecta

This is a case report of a 15-month-old patient with osteogenesis imperfecta (OI) who sustained atlanto-axial dislocation. Our objective is to report a unique case of traumatic atlanto-axial subluxation in a child with osteogenesis imperfecta associated with bilateral femoral fractures. The management is discussed. Atlanto-axial dislocation occurring with associated osteogenesis imperfecta is very rare. There have been no previous reported cases. A 15-month-old girl with osteogenesis imperfecta sustained a traumatic atlanto-axial dislocation. The child was followed-up through presentation, diagnosis, management and post-discharge. The initial diagnosis was confirmed with a CT scan. The patient was treated conservatively with a halo-traction for 4 weeks followed by a halo jacket for a further 4 weeks. Both appliances were fitted under general anaesthetic. An anatomical reduction was achieved. There was no neurological deficit at any stage. The child has had a successful outcome. She is asymptomatic with a full range of movement at the atlanto-axial joints at 9 months. In conclusion, this paper records our management of this rare problem.     

Cesarean delivery and colon resection in a patient with type III osteogenesis imperfecta

OBJECTIVE. Osteogenesis imperfecta is a connective tissue disorder that results from the inability to produce normal collagen. Eight types are described; type II is considered the lethal variant. Because of abnormal collagen production, these patients possess many anatomic and functional abnormalities. In addition to the obvious brittle bones, osteogenesis imperfecta patients may also possess respiratory, cardiac, spinal, endocrine, and hematologic abnormalities. These numerous derangements can lead to a challenging perioperative course. CASE REPORT. This report describes a case of a 27-year-old woman, G1P0 with history of type III osteogenesis imperfecta presenting at 31+ weeks with preterm premature rupture of membranes, lower extremity edema, and constipation. Because of progressive labor and cephalopelvic disproportion, an urgent cesarean section was performed under general anesthesia. Intraoperative coagulopathy was noted. After hemostasis was achieved, a colonic mass below the splenic flexure that measured 20 × 10 cm was revealed. General surgery was consulted intraoperatively, and a rectosigmoid resection was performed for a presumed colonic pseudo-obstruction. Patient tolerated the procedure well and was extubated at the completion of the case. The patient was discharged home on postoperative day 5. CLINICAL CHALLENGES. (a) Preoperative assessment of an osteogenesis imperfecta patient, (b) determination of anesthetic type, (c) management of hemorrhage/cardiovascular instability, and (d) management of hyperthermia. CONCLUSIONS. This case report illustrates that, with proper knowledge of this disease state, osteogenesis imperfecta patients can undergo a safe anesthetic during a potentially challenging combined cesarean section/colonic resection.     

An unconventional method of fixation of an isolated metaphyseal olecranon fracture in an adolescent with osteogenesis imperfecta

The authors present an unconventional method of fixation in an isolated metaphyseal fracture of the olecranon. The child was 14 years old and had osteogenesis imperfecta. The fracture was fixed with braided polyester sutures to avoid various complications; the end result was satisfactory.     

Fracture of the mandible in osteogenesis imperfecta

This article is a report on a fracture of the lower jaw in osteogenesis imperfecta. In this disease, fractures of the facial part of the skull are very rare, in contrast to fractures of the extremities; they may possibly occur in adults only if the bone is weakened by additional processes--in the present case, by an odontogenous cyst. In the case described here, successful treatment of the fracture could be effected via intraoral approach by means of a functionally stable osteosynthesis performed with plates.     

Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma

Background

Although a whole tumor cell vaccine strategy based on the synergistic action of granulocyte macrophage-colony-stimulating factor (GM-CSF) transduced tumor cells and CpG oligodeoxynucleotides induces potent tumor-specific immunity, such therapy is not curative in the face of large established tumors.

Purpose

The primary goal of this study was to determine if combining surgical resection of the tumor with whole tumor cell vaccination is an effective therapeutic strategy for established neuroblastoma. We also wished to determine if the phenotype of the immune response generated by this vaccine strategy was altered by the presence of bulky established tumor.

Methods

The murine neuroblastoma model was used in which syngeneic Neuro-2a was grown subcutaneously in A/J mouse. The whole tumor cell vaccine consisted of irradiated Neuro-2a as the vehicle for tumor antigens admixed with GM-CSF and CpG oligonucleotides (100 μg).

Results

In the presence of large tumors, dendritic cells were effectively activated by the vaccine, but secretion of intereferon-γ from vaccinated splenocytes in response to antigen stimulation was suppressed. The tumor's inhibitory effect on interferon-γ production from vaccinated splenocytes was reversed after resection of the primary tumor. The use of prepared GM-CSF-secreting bystander cells simplified production of an autologous whole tumor cell vaccine that was remarkably effective in curing large tumors when combined with tumor excision.

Conclusions

These findings suggest that at least part of the immunosuppressive effects of the cancer can be reversed after surgical excision of the primary tumor. Thus, in the context of minimal residual disease, this dendritic cell-targeted immunotherapeutic approach may prove effective for the treatment of neuroblastoma.     

Fractures of the acetabulum in osteogenesis imperfecta

We describe two patients aged 16 and 25 years with osteogenesis imperfecta who sustained displaced fractures of the acetabulum following minor trauma. The femoral heads were deformed by impact against the acetabular margin and both cases underwent surgical reconstruction. The quality of the bone and soft tissues made the operations challenging. There were potential complications specific to osteogenesis imperfecta, including bleeding, the creation of secondary fracture lines and shredding of the soft-tissue. The cases provide useful guidelines for addressing these difficulties.     

Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice

Summary

Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates.

Introduction

Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass.

Methods

To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity.

Results

+/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling.

Conclusions

Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

     

Percutaneous nailing in the management of osteogenesis imperfecta

Summary Marked deformities of the skeleton may develop in the severe form of osteogenesis imperfecta. Internal fixation can be effective in the treatment and prevention of fractures and deformities. Eight years ago, axial correction of deformities of the femora and tibiae by manual osteoclasis was carried out in a 7 year old girl in whom osteogenesis imperfecta had produced severe bowing of the long bones of the legs. Internal metal splints were introduced percutaneously to lie partially in, and partially alongside, the bone, to obtain fixation in the correct position. This treatment resulted in the prevention of refracture of the legs, while correction was maintained.

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Résumé D'importantes déformations du squelette peuvent apparaitre dans les formes graves de l'ostéogénèse imparfaite. La fixation interne est susceptible de traiter efficacement et de prévenir les fractures et les déformations. Il y a huit ans, une correction axiale des déformations des fémurs et des tibias a été réalisée par ostéoclasie manuelle chez une petite fille de 7 ans chez qui une ostéogénèse imparfaite avait entrainé de très importantes courbures des os longs des membres inférieurs. Des broches furent mises en place par voie percutanée, partiellement à l'intérieur des os et partiellement le long d'eux, afin d'obtenir une fixation en position correcte. Ce traitement a permis la prévention de nouvelles fractures, tandis que la correction était maintenue.

     

Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult

The musculoskeletal manifestations of mild forms of osteogenesis imperfecta are not well defined in the adult. The aim of this study was to characterize the musculoskeletal manifestations and resulting impairments reported by adults with mild osteogenesis imperfecta. For this task a survey of musculoskeletal symptoms and impairments was hosted on the Osteogenesis Imperfecta Foundation web site for 6 weeks. Survey responses are reported herein. There were 111 unduplicated, adult respondents (78 female). Mean age was 40.8 years. More than one-quarter of 3,410 lifetime fractures occurred in adulthood. Nearly half of respondents reported an established diagnosis of arthritis (usually osteoarthritis), and the majority of these reported some degree of impairment attributable to arthritis. Articular pain, stiffness and instability were dominant in the large, weight-bearing joints of the lower extremities. Back pain and scoliosis were common. Of the respondents, 15% required assistance with light physical tasks and personal care. Two-thirds reported joint hyper-mobility, and one-third reported a previous tendon rupture. Complex regional pain syndrome was rare. Respondents reported frequent use of medications known to have potential adverse skeletal effects. In spite of these concerns the majority rated their overall physical health as good or excellent. Adults with mild osteogenesis imperfecta continue to sustain fractures into adulthood, and the majority reports some functional impairment due to musculoskeletal issues. Significant impairment is not rare.     

Orthotopic tracheal transplantation in the murine model

BACKGROUND: Before tracheal transplantation can be clinically applied for the reconstruction of life-threatening airway defects, the immunobiology of this organ system must be better characterized. The availability of reagents and transgenic mice strains make the murine model ideal for this purpose. We have developed a reliable and reproducible method of orthotopic tracheal transplantation and characterized the kinetics of rejection. METHODS: Balb/c donor tracheal segments (five tracheal rings), were orthotopically transplanted into either syngeneic Balb/c recipients or allogeneic C57BL/6 recipients. Tracheal graft rejection was monitored by daily clinical airway assessment, in vivo cilia motility, and histologic examination using hematoxylin and eosin staining and CD8/CD4 immunohistochemistry. RESULTS: Two days after tracheal transplantation, allogenic recipients developed a persistent audible stridor that did not occur in the syngeneic experimental group. Whereas syngeneic tracheal autografts demonstrated normal mucociliary function after transplantation, allogeneic recipients failed to achieve normal mucociliary function. Normal histologic architecture persisted in the syngeneic grafts without evidence of lymphocytic infiltrate; however, the nonimmunosuppressed allogeneic grafts demonstrated a loss of normal ciliated respiratory epithelia and a CD8/CD4-positive lymphocytic infiltrate that peaked at 21 days after transplantation. CONCLUSIONS: The Balb/c (donor) to C57BL/6 (recipient) murine orthotopic tracheal transplant model offers a reliable method for the study of tracheal transplantation.     

Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4 weeks in male Col1a1^Jrt/+ mice, a model of severe dominant OI, starting either at 4 weeks (growing mice) or at 20 weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1^Jrt/+ mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model.     

Anesthesia for maxillary and mandibular osteotomies in osteogenesis imperfecta.

A 21-yr-old female suffering from osteogenesis imperfecta was anesthetized for correction of maxillary and mandibular deformities that had restricted her chewing. Preoperative assessment revealed a difficult intubation, restrictive lung disease secondary to bony deformities, and multiple repairs of fractures. Management of anesthesia for this operation--which is very rarely carried out in this disorder--is described along with a review of the problems of anesthesia associated with osteogenesis imperfecta.