Time-elapsed microstructural imaging of failure of the reverse shoulder implant.

BACKGROUND: Reverse Shoulder Arthroplasties (RSA) have become a primary choice for improving shoulder function and pain. However, the biomechanical failure mechanism of the humeral component is still unclear. The present study reports a novel protocol for microstructural imaging of the entire humerus implant under load before and after fracture. METHODS: A humerus specimen was obtained from a 75-year-old male donor. An expert surgeon implanted the specimen with a commonly used RSA implant (Aequalis reversed II, Stryker Orthopaedics, USA) and surgical procedure. The physiological glenohumeral contact force that maximized the distal implant migration was selected from a public repository ( orthoload.com ). Imaging and concomitant mechanical testing were performed using a large-volume micro-CT scanner (Nikon XT H 225 ST) and a custom-made compressive stage. Both when intact and once implanted, the specimen was tested under a pre-load and by imposing a constant deformation causing a physiological reaction load (650 N, 10 degrees adducted). The deformation of the implanted specimen was then increased up to fracture, which was identified by a sudden drop of the reaction force, and the specimen was then re-scanned. RESULTS: The specimen's stiffness decreased from 874 N/mm to 464 N/mm after implantation, producing movements of the bone-implant interface consistent with the implant's long-term stability reported in the literature. The micro-CT images displayed fracture of the tuberosity, caused by a combined compression and circumferential tension, induced by the distal migration of the implant. CONCLUSION: The developed protocol offers detailed information on implant mechanics under load relative to intact conditions and fracture, providing insights into the failure mechanics of RSA implants. This protocol can be used to inform future implant design and surgical technique improvements.

Three-dimensional cortical and trabecular bone microstructure of the proximal ulna.

INTRODUCTION: The three-dimensional (3D) microstructure of the cortical and trabecular bone of the proximal ulna has not yet been described by means of high-resolution 3D imaging. An improved characterization can provide a better understanding of their relative contribution to resist impact load. The aim of this study is to describe the proximal ulna bone microstructure using micro-computed tomography (micro-CT) and relate it to gross morphology and function. MATERIALS AND METHODS: Five dry cadaveric human ulnae were scanned by micro-CT (17 µm/voxel, isotropic). Both qualitative and quantitative assessments were performed on sagittal image stacks. The cortical thickness of the trochlear notch and the trabecular bone microstructure were measured in the olecranon, bare area and coronoid. RESULTS: Groups of trabecular struts starting in the bare area, spanning towards the anterior and posterior side of the proximal ulna, were observed; within the coronoid, the trabeculae were orthogonal to the joint surface. Consistently among the ulnae, the coronoid showed the highest cortical thickness (1.66 ± 0.59 mm, p = 0.04) and the olecranon the lowest (0.33 ± 0.06 mm, p = 0.04). The bare area exhibited the highest bone volume fraction (BV/TV = 43.7 ± 22.4%), trabecular thickness (Tb.Th = 0.40 ± 0.09 mm) and lowest structure model index (SMI = - 0.28 ± 2.20, indicating plate-like structure), compared to the other regions (p = 0.04). CONCLUSIONS: Our microstructural results suggest that the bare area is the region where most of the loading of the proximal ulna is concentrated, whereas the coronoid, together with its anteromedial facet, is the most important bony stabilizer of the elbow joint. Studying the proximal ulna bone microstructure helps understanding its possible everyday mechanical loading conditions and potential fractures. LEVEL OF EVIDENCE: N.A.

Regional differences in the three-dimensional bone microstructure of the radial head: implications for observed fracture patterns.

INTRODUCTION: A characterization of the internal bone microstructure of the radial head could provide a better understanding of commonly occurring fracture patterns frequently involving the (antero)lateral quadrant, for which a clear explanation is still lacking. The aim of this study is to describe the radial head bone microstructure using micro-computed tomography (micro-CT) and to relate it to gross morphology, function and possible fracture patterns. MATERIALS AND METHODS: Dry cadaveric human radii were scanned by micro-CT (17 µm/pixel, isotropic). The trabecular bone microstructure was quantified on axial image stacks in four quadrants: the anterolateral (AL), posterolateral (PL), posteromedial (PM) and anteromedial (AM) quadrant. RESULTS: The AL and PL quadrants displayed the significantly lowest bone volume fraction and trabecular number (BV/TV range 12.3-25.1%, Tb.N range 0.73-1.16 mm-1) and highest trabecular separation (Tb.Sp range 0.59-0.82 mm), compared to the PM and AM quadrants (BV/TV range 19.9-36.9%, Tb.N range 0.96-1.61 mm-1, Tb.Sp range 0.45-0.74 mm) (p = 0.03). CONCLUSIONS: Our microstructural results suggest that the lateral side is the "weaker side", exhibiting lower bone volume faction, less trabeculae and higher trabecular separation, compared to the medial side. As the forearm is pronated during most falls, the underlying bone microstructure could explain commonly observed fracture patterns of the radial head, particularly more often involving the AL quadrant. If screw fixation in radial head fractures is considered, surgeons should take advantage of the "stronger" bone microstructure of the medial side of the radial head, should the fracture line allow this.

Relationships between tibial articular cartilage, in vivo external joint moments and static alignment in end-stage knee osteoarthritis: A micro-CT study.

Biomechanical factors (e.g., joint loading) have a significant role in the progression of osteoarthritis (OA). However, some relationships between in vivo joint loading indices and tibial cartilage thickness are conflicting. This study investigated relationships between pre-operative in vivo external knee joint moments, joint alignment and regional tibial cartilage thickness using micro-CT in subjects with end-stage knee OA. Tibial plateaus from 25 patients that underwent knee replacement for OA were micro-CT scanned (17 µm/voxel). Prior to surgery, subjects underwent gait analysis to calculate external knee moments. The mechanical axis deviation (MAD) was obtained from pre-operative radiographs. Cartilage thickness (Cart.Th) was analyzed from micro-CT images, in anteromedial, anterolateral, posteromedial and posterolateral subregions of interest. Medial-to-lateral Cart.Th ratios were also explored. Relationships between Cart.Th and joint loading indices were examined using Pearson's correlations. Significant correlations were found between Cart.Th and joint loading indices, positive anteromedially with the first peak knee adduction moment (r = 0.55, p < 0.01) and external rotation moment (ERM; r = 0.52, p < 0.01), and negative with MAD (r = -0.76, p < 0.001). In the lateral regions, these correlations had opposite signs. The medial-to-lateral Cart.Th ratio correlated strongly with ERM (r = 0.63, p = 0.001) and MAD (r = -0.75, p < 0.001). Joint loading indices correlated with regional cartilage thickness values and their medial-to-lateral ratios in end-stage knee OA subjects, with higher regional loads corresponding to thinner cartilage. These relationships have the opposite sign compared to the subchondral bone microarchitecture found in our previous study on the same specimens, which may suggest a complementary bone-cartilage interplay in response to loading.

Effects of Mild and Moderate Monoclonal Antibody Dose on Inflammation, Bone Loss, and Activation of the Central Nervous System in a Female Collagen Antibody-induced Arthritis Mouse Model.

Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice (n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV; (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue; and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.

Time dependent loss of trabecular bone in human tibial plateau fractures.

We investigated if time between injury and surgery affects cancellous bone properties in patients suffering tibial plateau fractures (TPF), in terms of structural integrity and gene expression controlling bone loss. A cohort of 29 TPF, operated 1-17 days post-injury, had biopsies from the fracture and an equivalent contralateral limb site, at surgery. Samples were assessed using micro-computed tomography and real-time RT-PCR analysis for the expression of genes known to be involved in bone remodeling and fracture healing. Significant decreases in the injured vs control side were observed for bone volume fraction (BV/TV, -13.5 ± 6.0%, p = 0.011), trabecular number (Tb.N, -10.5 ± 5.9%, p = 0.041) and trabecular thickness (Tb.Th, -4.6 ± 2.5%, p = 0.033). Changes in these parameters were more evident in patients operated 5-17 days post-injury, compared to those operated in the first 4 days post-injury. A significant negative association was found between Tb.Th (r = -0.54, p < 0.01) and BV/TV (r = -0.39, p < 0.05) in relation to time post-injury in the injured limb. Both BV/TV and Tb.Th were negatively associated with expression of key molecular markers of bone resorption, CTSK, ACP5, and the ratio of RANKL:OPG mRNA. These structure/gene expression relationships did not exist in the contralateral tibial plateau of these patients. This study demonstrated that there is a significant early time-dependent bone loss in the proximal tibia after TPF. This bone loss was significantly associated with altered expression of genes typically involved in the process of osteoclastic bone resorption but possibly also bone resorption by osteocytes. The mechanism of early bone loss in such fractures should be a subject of further investigation. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2865-2875, 2018.

Discrete tomography in an in vivo small animal bone study.

This study aimed at assessing the feasibility of a discrete algebraic reconstruction technique (DART) to be used in in vivo small animal bone studies. The advantage of discrete tomography is the possibility to reduce the amount of X-ray projection images, which makes scans faster and implies also a significant reduction of radiation dose, without compromising the reconstruction results. Bone studies are ideal for being performed with discrete tomography, due to the relatively small number of attenuation coefficients contained in the image [namely three: background (air), soft tissue and bone]. In this paper, a validation is made by comparing trabecular bone morphometric parameters calculated from images obtained by using DART and the commonly used standard filtered back-projection (FBP). Female rats were divided into an ovariectomized (OVX) and a sham-operated group. In vivo micro-CT scanning of the tibia was done at baseline and at 2, 4, 8 and 12 weeks after surgery. The cross-section images were reconstructed using first the full set of projection images and afterwards reducing them in number to a quarter and one-sixth (248, 62, 42 projection images, respectively). For both reconstruction methods, similar changes in morphometric parameters were observed over time: bone loss for OVX and bone growth for sham-operated rats, although for DART the actual values were systematically higher (bone volume fraction) or lower (structure model index) compared to FBP, depending on the morphometric parameter. The DART algorithm was, however, more robust when using fewer projection images, where the standard FBP reconstruction was more prone to noise, showing a significantly bigger deviation from the morphometric parameters obtained using all projection images. This study supports the use of DART as a potential alternative method to FBP in X-ray micro-CT animal studies, in particular, when the number of projections has to be drastically minimized, which directly reduces scanning time and dose.

Quantifying shape changes of silicone breast implants in a murine model using in vivo micro-CT.

A major complication of silicone breast implants is the formation of a capsule around the implant known as capsular contracture which results in the distortion of the implant. Recently, a mouse model for studying capsular contracture was examined using micro-computed tomography (micro-CT), however, only qualitative changes were reported. The aim of this study was to develop a quantitative method for comparing the shape changes of silicone implants using in vivo micro-CT. Mice were bilaterally implanted with silicone implants and underwent ionizing radiation to induce capsular contracture. On day 28 post-surgery mice were examined in vivo using micro-CT. The reconstructed cross-section images were visually inspected to identify distortion. Measurements were taken in 2D and 3D to quantify the shape of the implants in the normal (n = 11) and distorted (n = 5) groups. The degree of anisotropy was significantly higher in the distorted implants in the transaxial view (0.99 vs. 1.19, p = 0.002) and the y-axis lengths were significantly shorter in the sagittal (9.27 mm vs. 8.55 mm, p = 0.015) and coronal (9.24 mm vs. 8.76 mm, p = 0.031) views, indicating a deviation from the circular cross-section and shortening of the long axis. The 3D analysis revealed a significantly lower average thickness (sphere-fitting method) in distorted implants (6.86 mm vs. 5.49 mm, p = 0.002), whereas the volume and surface area did not show significant changes. Statistically significant differences between normal and distorted implants were found in 2D and 3D using distance measurements performed via micro-CT. This objective analysis method can be useful for a range of studies involving deformable implants using in vivo micro-CT. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1447-1452, 2017.

The Etiology and Pathogenesis of Kienböck Disease.

Kienböck disease is a condition that typically occurs in the "at-risk" patient, in the "at-risk" aspect of the proximal condyle of the "at-risk" lunate. In the active male, repetitive loading causes the stress fracture that commences in the single layer proximal subchondral bone plate. The lunate fracture commences at the point the lunate cantilevers over the edge of the distal radius, and then takes on the shape of the radius. We postulate that the stress fracture violates the parallel veins of the venous subarticular plexus-leading to localized venous hypertension and subsequent ischemia and edema of the fatty marrow. The increased osseous compartment pressure further potentiates the venous obstruction, producing avascular necrosis. If the fracture remains localized, it can heal or settle into a stable configuration, so that the wrist remains functional. Fractures of the subchondral bone plate produce irregularity of the lunate articular surfaces and secondary "kissing lesions" of the lunate facet and capitate, and subsequent degeneration. The lunate collapses when the fracture is comminuted, or there is disruption of the spanning trabeculae or a coronal fracture. The secondary effect of the lunate collapse is proximal migration of the capitate between the volar and dorsal fragments, producing collapse of the entire central column. The proximal carpal row is now unstable, and is similar to scapholunate instability, where the capitate migrates between the scaphoid and lunate. The scaphoid is forced into flexion by the trapezium, however, degeneration of the scaphoid and scaphoid facet only occurs in late disease or following failed surgery. In Kienböck disease, the secondary effects of the collapsing lunate are a "compromised" wrist, including: deformity and collapse of the central column, degeneration of the central column (perilunate) articulations, proximal row instability (i.e., between the central and radial columns), and degeneration of the radial column.

Erratum: The Etiology and Pathogenesis of Kienböck Disease.

[This corrects the article DOI: 10.1055/s-0036-1583755.].

Parthenolide reduces empty lacunae and osteoclastic bone surface resorption induced by polyethylene particles in a murine calvarial model of peri-implant osteolysis.

The study aimed to determine the effects of parthenolide (PAR) on bone volume (BV) and bone surface resorption as assessed by live-animal microcomputed tomography (µCT) and possible osteocyte death as indicated by empty lacunae histologically in polyethylene (PE) particle-induced calvarial osteolysis in mice. Baseline µCT scans were conducted 7 days preimplantation of 2 × 10(8) PE particles/mL over the calvariae (day 0). PAR at 1 mg/kg/day was subcutaneously injected on days 0, 4, 7, and 10. At day 14, BV and surface resorption was analyzed with µCT. Calvarial tissue was processed for histomorphometric osteocyte evaluation. Serum was analyzed for type-1 carboxy-terminal collagen crosslinks (CTX-1) and osteoclast associated receptor (OSCAR) levels by ELISA. PE significantly decreased BV (p = 0.0368), increased surface bone resorption area (p = 0.0022), and increased the percentage of empty lacunae (p = 0.0043). Interestingly, PAR significantly reduced the resorption surface area (p = 0.0022) and the percentage of empty osteocyte lacunae (p = 0.0087) in the PE-calvariae, but it did not affect BV, serum CTX-1 or OSCAR levels. The ability of PAR to inhibit PE-induced surface bone erosion may better reflect the in vivo situation, where bone resorption occurs on the surface at the bone-implant interface and may also be related to the role of osteocytes in this pathology.

Modic (endplate) changes in the lumbar spine: bone micro-architecture and remodelling.

PURPOSE: In the literature, inter-vertebral MRI signal intensity changes (Modic changes) were associated with corresponding histological observations on endplate biopsies. However, tissue-level studies were limited. No quantitative histomorphometric study on bone biopsies has yet been conducted for Modic changes. The aim of this study was to characterise the bone micro-architectural parameters and bone remodelling indices associated with Modic changes. METHODS: Forty patients suffering from disabling low back pain, undergoing elective spinal surgery, and exhibiting Modic changes on MRI (Modic 1, n = 9; Modic 2, n = 25; Modic 3, n = 6), had a transpedicular vertebral body biopsy taken of subchondral bone. Biopsies were first examined by micro-CT, for 3D morphometric analysis of bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular separation, trabecular number, and structure model index. Then, samples underwent histological analysis, for determination of bone remodelling indices: osteoid surface to bone surface ratio (OS/BS), eroded surface to bone surface (ES/BS) and osteoid surface to eroded surface ratio (OS/ES). RESULTS: Micro-CT analysis revealed significantly higher BV/TV (up to 70% increase, p < 0.01) and Tb.Th (up to +57%, p < 0.01) in Modic 3 biopsies, compared to Modic 1 and 2. Histological analysis showed significantly lower OS/BS in Modic 2 biopsies (more than 28% decrease, p < 0.05) compared to 1 and 3. ES/BS progressively decreased from Modic 1 to 2 to 3, whereas OS/ES progressively increased with significantly higher values in Modic 3 (up to 159% increase, p < 0.05) than in Modic 1 and 2. CONCLUSIONS: Significant differences were found in bone micro-architectural parameters and remodelling indices among Modic types. Modic 1 biopsies had evidence of highest bone turnover, possibly due to an inflammatory process; Modic 2 biopsies were consistent with a reduced bone formation/remodelling stage; Modic 3 biopsies suggested a more stable sclerotic phase, with significantly increased BV/TV and Tb.Th compared to Modic 1 and 2, linked to increased bone formation and reduced resorption.

Pullout strength of cancellous screws in human femoral heads depends on applied insertion torque, trabecular bone microarchitecture and areal bone mineral density.

For cancellous bone screws, the respective roles of the applied insertion torque (TInsert) and of the quality of the host bone (microarchitecture, areal bone mineral density (aBMD)), in contributing to the mechanical holding strength of the bone-screw construct (FPullout), are still unclear. During orthopaedic surgery screws are tightened, typically manually, until adequate compression is attained, depending on surgeons' manual feel. This corresponds to a subjective insertion torque control, and can lead to variable levels of tightening, including screw stripping. The aim of this study, performed on cancellous screws inserted in human femoral heads, was to investigate which, among the measurements of aBMD, bone microarchitecture, and the applied TInsert, has the strongest correlation with FPullout. Forty six femoral heads were obtained, over which microarchitecture and aBMD were evaluated using micro-computed tomography and dual X-ray absorptiometry. Using an automated micro-mechanical test device, a cancellous screw was inserted in the femoral heads at TInsert set to 55% to 99% of the predicted stripping torque beyond screw head contact, after which FPullout was measured. FPullout exhibited strongest correlations with TInsert (R=0.88, p<0.001), followed by structure model index (SMI, R=-0.81, p<0.001), bone volume fraction (BV/TV, R=0.73, p<0.001) and aBMD (R=0.66, p<0.01). Combinations of TInsert with microarchitectural parameters and/or aBMD did not improve the prediction of FPullout. These results indicate that, for cancellous screws, FPullout depends most strongly on the applied TInsert, followed by microarchitecture and aBMD of the host bone. In trabecular bone, screw tightening increases the holding strength of the screw-bone construct.

MHC class II transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity.

The molecular networks controlling bone homeostasis are not fully understood. The common evolution of bone and adaptive immunity encourages the investigation of shared regulatory circuits. MHC Class II Transactivator (CIITA) is a master transcriptional co-activator believed to be exclusively dedicated for antigen presentation. CIITA is expressed in osteoclast precursors, and its expression is accentuated in osteoporotic mice. We thus asked whether CIITA plays a role in bone biology. To this aim, we fully characterized the bone phenotype of two mouse models of CIITA overexpression, respectively systemic and restricted to the monocyte-osteoclast lineage. Both CIITA-overexpressing mouse models revealed severe spontaneous osteoporosis, as assessed by micro-computed tomography and histomorphometry, associated with increased osteoclast numbers and enhanced in vivo bone resorption, whereas osteoblast numbers and in vivo bone-forming activity were unaffected. To understand the underlying cellular and molecular bases, we investigated ex vivo the differentiation of mutant bone marrow monocytes into osteoclasts and immune effectors, as well as osteoclastogenic signaling pathways. CIITA-overexpressing monocytes differentiated normally into effector macrophages or dendritic cells but showed enhanced osteoclastogenesis, whereas CIITA ablation suppressed osteoclast differentiation. Increased c-fms and receptor activator of NF-κB (RANK) signaling underlay enhanced osteoclast differentiation from CIITA-overexpressing precursors. Moreover, by extending selected phenotypic and cellular analyses to additional genetic mouse models, namely MHC Class II deficient mice and a transgenic mouse line lacking a specific CIITA promoter and re-expressing CIITA in the thymus, we excluded MHC Class II expression and T cells from contributing to the observed skeletal phenotype. Altogether, our study provides compelling genetic evidence that CIITA, the molecular switch of antigen presentation, plays a novel, unexpected function in skeletal homeostasis, independent of MHC Class II expression and T cells, by exerting a selective and intrinsic control of osteoclast differentiation and bone resorption in vivo.

Micro-CT examination of human bone: from biopsies towards the entire organ.

Micro-CT systems are available that facilitate ex vivo examinations of human specimens as big as entire vertebrae, with spatial resolutions in the 10-micrometer range. This opens a new way for looking at entire bones in 3D. Accurate description of the internal microarchitecture of the entire organ can be obtained, at spatial resolutions previously achievable only on excised biopsies. These high resolution scans produce large datasets and come with costs and benefits, which have to be considered in the successful planning of an experiment. The aim of this paper is to present examples of human vertebrae scanned at high resolution (17 µm/pixel), allowing the visualization and quantification of the microarchitecture, and to discuss some aspects of using high resolution scans of such large specimens. The datasets were down-sampled to 34 µm and 68 µm pixel size, and their morphometric parameters compared to those obtained at 17 µm pixel size, in relation to data size and calculation time.

Application of in vivo micro-computed tomography in the temporal characterisation of subchondral bone architecture in a rat model of low-dose monosodium iodoacetate-induced osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is a complex, multifactorial joint disease affecting both the cartilage and the subchondral bone. Animal models of OA aid in the understanding of the pathogenesis of OA and testing suitable drugs for OA treatment. In this study we characterized the temporal changes in the tibial subchondral bone architecture in a rat model of low-dose monosodium iodoacetate (MIA)-induced OA using in vivo micro-computed tomography (CT). METHODS: Male Wistar rats received a single intra-articular injection of low-dose MIA (0.2 mg) in the right knee joint and sterile saline in the left knee joint. The animals were scanned in vivo by micro-CT at two, six, and ten weeks post-injection, analogous to early, intermediate, and advanced stages of OA, to assess architectural changes in the tibial subchondral bone. The articular cartilage changes in the tibiae were assessed macroscopically and histologically at ten weeks post-injection. RESULTS: Interestingly, tibiae of the MIA-injected knees showed significant bone loss at two weeks, followed by increased trabecular thickness and separation at six and ten weeks. The trabecular number was decreased at all time points compared to control tibiae. The tibial subchondral plate thickness of the MIA-injected knee was increased at two and six weeks and the plate porosity was increased at all time points compared to control. At ten weeks, histology revealed loss of proteoglycans, chondrocyte necrosis, chondrocyte clusters, cartilage fibrillation, and delamination in the MIA-injected tibiae, whereas the control tibiae showed no changes. Micro-CT images and histology showed the presence of subchondral bone sclerosis, cysts, and osteophytes. CONCLUSIONS: These findings demonstrate that the low-dose MIA rat model closely mimics the pathological features of progressive human OA. The low-dose MIA rat model is therefore suitable to study the effect of therapeutic drugs on cartilage and bone in a non-trauma model of OA. In vivo micro-CT is a non-destructive imaging technique that can track structural changes in the tibial subchondral bone in this animal model, and could also be used to track changes in bone in preclinical drug intervention studies for OA treatments.

In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.

Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [alpha1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases.