Antibodies to recombinant human alpha-L-iduronidase prevent disease correction in cortical bone in MPS I mice.

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by deficiency of the enzyme α-l-iduronidase (IDUA). Failure of enzyme replacement therapy (ERT) to treat skeletal disease may be due to development of anti-IDUA antibodies, found previously to alter tissue distribution of ERT in animal models. To test this hypothesis, immunocompromised (non-obese diabetic [NOD]-severe combined immunodeficiency [SCID]) MPS I mice were treated with weekly ERT from birth (ERT alone).

Multi-organ phenotypes in mice lacking latent TGFβ binding protein 2 (LTBP2).

Background: Latent TGFβ binding protein-2 (LTBP2) is a fibrillin 1 binding component of the microfibril. LTBP2 is the only LTBP protein that does not bind any isoforms of TGFβ, although it may interfere with the function of other LTBPs or interact with other signaling pathways.

Results: Here, we investigate mice lacking Ltbp2 (Ltbp2 ) and identify multiple phenotypes that impact bodyweight and fat mass, and affect bone and skin development.

Cortical bone relationships are maintained regardless of sex and diet in a large population of LGXSM advanced intercross mice.

Introduction: Knowledge of bone structure-function relationships in mice has been based on relatively small sample sets that limit generalizability. We sought to investigate structure-function relationships of long bones from a large population of genetically diverse mice. Therefore, we analyzed previously published data from the femur and radius of male and female mice from the F34 generation of the Large-by-Small advanced intercross line (LGXSM AI), which have over a two-fold continuous spread of bone and body sizes (Silva et al.

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling.

Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment.

Osteoblast-Specific Wnt Secretion Is Required for Skeletal Homeostasis and Loading-Induced Bone Formation in Adult Mice.

Wnt signaling is critical to many aspects of skeletal regulation, but the importance of Wnt ligands in the bone anabolic response to mechanical loading is not well established. Recent transcriptome profiling studies by our laboratory and others show that mechanical loading potently induces genes encoding Wnt ligands, including Wnt1 and Wnt7b. Based on these findings, we hypothesized that mechanical loading stimulates adult bone formation by inducing Wnt ligand expression.

Estimation of load conditions and strain distribution for in vivo murine tibia compression loading using experimentally informed finite element models.

The murine tibia compression model, is the gold standard for studying bone adaptation due to mechanical loading in vivo. Currently, a key limitation of the experimental protocol and associated finite element (FE) models is that the exact load transfer, and consequently the loading conditions on the tibial plateau, is unknown. Often in FE models, load is applied to the tibial plateau based on inferences from micro-computed tomography (μCT).

MicroCT for Scanning and Analysis of Mouse Bones.

The purpose of this Chapter is to present a detailed description of methods for performing bone Micro-Computed Tomography (microCT) scanning and analysis. MicroCT is an x-ray imaging method capable of visualizing bone at the micro-structural scale, that is, 1-100 µm resolution. MicroCT is the gold-standard method for assessment of 3D bone morphology in studies of small animals.

Proliferating osteoblasts are necessary for maximal bone anabolic response to loading in mice.

Following mechanical loading, osteoblasts may arise via activation, differentiation, or proliferation to form bone. Our objective was to ablate proliferating osteoblast lineage cells in order to investigate the importance of these cells as a source for loading-induced bone formation. We utilized 3.

Old Mice Have Less Transcriptional Activation But Similar Periosteal Cell Proliferation Compared to Young-Adult Mice in Response to in vivo Mechanical Loading.

Mechanical loading is a potent strategy to induce bone formation, but with aging, the bone formation response to the same mechanical stimulus diminishes. Our main objectives were to (i) discover the potential transcriptional differences and (ii) compare the periosteal cell proliferation between tibias of young-adult and old mice in response to strain-matched mechanical loading. First, to discover potential age-related transcriptional differences, we performed RNA sequencing (RNA-seq) to compare the loading responses between tibias of young-adult (5-month) and old (22-month) C57BL/6N female mice following 1, 3, or 5 days of axial loading (loaded versus non-loaded).

Congenital lipodystrophy induces severe osteosclerosis.

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals.

Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice.

Obesity is generally protective against osteoporosis and bone fracture. However, recent studies indicate that the influence of obesity on the skeleton is complex and can be detrimental. We evaluated the effects of a high-fat, obesogenic diet on the femur and radius of 1100 mice (males and females) from the Large-by-Small advanced intercross line (F generation).

Evaluation of loading parameters for murine axial tibial loading: Stimulating cortical bone formation while reducing loading duration.

Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model.

Mechanical comparison of iliosacral reconstruction techniques after sarcoma resection.

Background: Reconstruction of iliosacral defects following oncologic resection is a difficult clinical problem associated with a high incidence of failure. Technical approaches to this problem are heterogeneous and evidence supporting specific techniques is sparse. Maximizing construct stability may improve union rates and functional outcomes.

Activation of Wnt Signaling by Mechanical Loading Is Impaired in the Bone of Old Mice.

Aging diminishes bone formation engendered by mechanical loads, but the mechanism for this impairment remains unclear. Because Wnt signaling is required for optimal loading-induced bone formation, we hypothesized that aging impairs the load-induced activation of Wnt signaling. We analyzed dynamic histomorphometry of 5-month-old, 12-month-old, and 22-month-old C57Bl/6JN mice subjected to multiple days of tibial compression and corroborated an age-related decline in the periosteal loading response on day 5.

Aging diminishes lamellar and woven bone formation induced by tibial compression in adult C57BL/6.

Aging purportedly diminishes the ability of the skeleton to respond to mechanical loading, but recent data show that old age did not impair loading-induced accrual of bone in BALB/c mice. Here, we hypothesized that aging limits the response of the tibia to axial compression over a range of adult ages in the commonly used C57BL/6. We subjected the right tibia of old (22 month), middle-aged (12 month) and young-adult (5 month) female C57BL/6 mice to peak periosteal strains (measured near the mid-diaphysis) of -2200 με and -3000 με (n=12-15/age/strain) via axial tibial compression (4 Hz, 1200 cycles/day, 5 days/week, 2 weeks).

Experimental and finite element analysis of strains induced by axial tibial compression in young-adult and old female C57Bl/6 mice.

Axial compression of the mouse tibia is used to study strain-adaptive bone (re)modeling. In some studies, comparisons between mice of different ages are of interest. We characterized the tibial deformation and force-strain relationships in female C57Bl/6 mice at 5-, 12- and 22-months age.

Adaptation of tibial structure and strength to axial compression depends on loading history in both C57BL/6 and BALB/c mice.

Tibial compression can increase murine bone mass. However, loading protocols and mouse strains differ between studies, which may contribute to conflicting results. We hypothesized that bone accrual is influenced more by loading history than by mouse strain or animal handling.

Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice.

The gap junction protein, connexin43 (Cx43) is involved in mechanotransduction in bone. Recent studies using in vivo models of conditional Cx43 gene (Gja1) deletion in the osteogenic linage have generated inconsistent results, with Gja1 ablation resulting in either attenuated or enhanced response to mechanical load, depending upon the skeletal site examined or the type of load applied. To gain further insights on Cx43 and mechanotransduction, we examined bone formation response at both endocortical and periosteal surfaces in 2-month-old mice with conditional Gja1 ablation driven by the Dermo1 promoter (cKO).

Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.

There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice.

The effects of screw length on stability of simulated osteoporotic distal radius fractures fixed with volar locking plates.

Purpose: Volar plating for distal radius fractures has caused extensor tendon ruptures resulting from dorsal screw prominence. This study was designed to determine the biomechanical impact of placing unicortical distal locking screws and pegs in an extra-articular fracture model.

Methods: We applied volar-locking distal radius plates to 30 osteoporotic distal radius models.

Connexin43 deficiency reduces the sensitivity of cortical bone to the effects of muscle paralysis.

We have shown previously that the effect of mechanical loading on bone depends in part on connexin43 (Cx43). To determine whether Cx43 is also involved in the effect of mechanical unloading, we have used botulinum toxin A (BtxA) to induce reversible muscle paralysis in mice with a conditional deletion of the Cx43 gene in osteoblasts and osteocytes (cKO). BtxA injection in hind limb muscles of wild-type (WT) mice resulted in significant muscle atrophy and rapid loss of trabecular bone.

Low-magnitude whole-body vibration does not enhance the anabolic skeletal effects of intermittent PTH in adult mice.

Whole-body vibration (WBV) is a low-magnitude mechanical stimulus that may be anabolic for bone, yet we recently found that WBV did not improve bone properties in adult mice. Because intermittent parathyroid hormone (PTH) enhances the anabolic effects of high-magnitude skeletal loading, we sought to determine the skeletal effects of WBV in combination with PTH. Seven-month-old male BALB/c mice were assigned to six groups (n = 13-14/group) based on magnitude of applied acceleration (0 or 0.

Evaluation of acute fixation strength for mechanical tacking devices and fibrin sealant versus polypropylene suture for laparoscopic ventral hernia repair.

Background: The purpose of this comparative study is to evaluate the acute fixation strength of mechanical tacking devices and fibrin sealant against polypropylene suture for laparoscopic ventral hernia repair.

Methods: Three metallic mechanical tacking devices (ProTack, Salute, EndoANCHOR), 4 absorbable tacking devices (AbsorbaTack, PermaSorb, I-Clip, and SorbaFix), and 2 types of fibrin sealant (Tisseel, Artiss) were compared with 0-polypropylene suture. Three constructs from each device or an amount of sealant sufficient to cover a 3 × 3 cm(2) area were used to affix a 4 × 3 cm piece of absorbable barrier-coated mesh (Proceed, Ethicon, Inc) to the peritoneal surface of porcine abdominal wall.

Microfibril-associated glycoprotein-1, an extracellular matrix regulator of bone remodeling.

MAGP1 is an extracellular matrix protein that, in vertebrates, is a ubiquitous component of fibrillin-rich microfibrils. We previously reported that aged MAGP1-deficient mice (MAGP1Delta) develop lesions that are the consequence of spontaneous bone fracture. We now present a more defined bone phenotype found in MAGP1Delta mice.

Aged mice have enhanced endocortical response and normal periosteal response compared with young-adult mice following 1 week of axial tibial compression.

With aging, the skeleton may lose its ability to respond to positive mechanical stimuli. We hypothesized that aged mice are less responsive to loading than young-adult mice. We subjected aged (22 months) and young-adult (7 months) BALB/c male mice to daily bouts of axial tibial compression for 1 week and evaluated cortical and trabecular responses using micro-computed tomography (µCT) and dynamic histomorphometry.