Sustained local ionic homeostatic imbalance caused by calcification modulates inflammation to trigger heterotopic ossification.

Heterotopic ossification (HO) is a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues. Despite being a frequent complication of orthopedic and trauma surgery, brain and spinal injury, the etiology of HO is poorly understood. The aim of this study is to evaluate the hypothesis that a sustained local ionic homeostatic imbalance (SLIHI) created by mineral formation during tissue calcification modulates inflammation to trigger HO.

A BMP/Activin A Chimera Induces Posterolateral Spine Fusion in Nonhuman Primates at Lower Concentrations Than BMP-2.

Background: Supraphysiologic bone morphogenetic protein (BMP)-2 concentrations are required to induce spinal fusion. In this study, a BMP-2/BMP-6/activin A chimera (BV-265), optimized for BMP receptor binding, delivered in a recombinant human collagen:CDHA [calcium-deficient hydroxyapatite] porous composite matrix (CM) or bovine collagen:CDHA granule porous composite matrix (PCM), engineered for optimal BV-265 retention and guided tissue repair, was compared with BMP-2 delivered in a bovine absorbable collagen sponge (ACS) wrapped around a MASTERGRAFT Matrix (MM) ceramic-collagen rod (ACS:MM) in a nonhuman primate noninstrumented posterolateral fusion (PLF) model.

Methods: In vivo retention of 125I-labeled-BV-265/CM or PCM was compared with 125I-labeled-BMP-2/ACS or BMP-2/buffer in a rat muscle pouch model using scintigraphy.

Activation of Bone Remodeling Compartments in BMP-2-Injected Knees Supports a Local Vascular Mechanism for Arthritis-Related Bone Changes.

Background: Synovial membrane-derived factors are implicated in arthritis-related bone changes. The route that synovial factors use to access subchondral bone and the mechanisms responsible for these bone changes remain unclear. A safety study involving intra-articular injection of bone morphogenetic protein-2 (BMP-2)/calcium phosphate matrix (CPM) or CPM addresses these issues.

Tyrosine kinase Eph receptor A6 sensitizes glioma-initiating cells towards bone morphogenetic protein-induced apoptosis.

Bone morphogenetic protein (BMP) signaling plays important roles in glioblastoma multiforme (GBM), a lethal form of brain tumor. BMP reduces GBM tumorigenicity through its differentiation- and apoptosis-inducing effects on glioma-initiating cells (GIC). However, some GIC do not respond to the tumor suppressive effects of BMP.

A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix.

Bone morphogenetic protein (BMP)/carriers approved for orthopedic procedures achieve efficacy superior or equivalent to autograft bone. However, required supraphysiological BMP concentrations have been associated with potential local and systemic adverse events. Suboptimal BMP/receptor binding and rapid BMP release from approved carriers may contribute to these outcomes.

Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction.

Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound.

A myostatin and activin decoy receptor enhances bone formation in mice.

Myostatin is a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGFβ) super-family of secreted differentiation factors. Myostatin is a negative regulator of muscle mass as shown by increased muscle mass in myostatin deficient mice. Interestingly, these mice also exhibit increased bone mass suggesting that myostatin may also play a role in regulating bone mass.

Surface-mediated bone tissue morphogenesis from tunable nanolayered implant coatings.

The functional success of a biomedical implant critically depends on its stable bonding with the host tissue. Aseptic implant loosening accounts for more than half of all joint replacement failures. Various materials, including metals and plastic, confer mechanical integrity to the device, but often these materials are not suitable for direct integration with the host tissue, which leads to implant loosening and patient morbidity.

The mechanical consequences of load bearing in the equine third metacarpal across speed and gait: the nonuniform distributions of normal strain, shear strain, and strain energy density.

Distributions of normal strain, shear strain, and strain energy density (SED) were determined across the midshaft of the third metacarpal (MCIII, or cannon bone) of 3 adult thoroughbred horses as a function of speed and gait. A complete characterization of the mechanical demands of the bone made through the stride and from mild through the extremes of locomotion was possible by using three 3-element rosette strain gauges bonded at the diaphyseal midshaft of the MCIII and evaluating the strain output with beam theory and finite element analysis. Mean ± sd values of normal strain, shear strain, and SED increased with speed and peaked during a canter (-3560±380 microstrain, 1760±470 microstrain, and 119±23 kPa, respectively).

Intraosseous injection of rhBMP-2/calcium phosphate matrix improves bone structure and strength in the proximal aspect of the femur in chronic ovariectomized nonhuman primates.

Background: Osteoporosis results in a decrease in bone density, bone quality, and strength throughout the skeleton. Despite systemic therapies, the morbidity and mortality that are associated with hip fractures remain a major consequence of osteoporosis.

Methods: We used fourteen chronic ovariectomized female cynomolgus monkeys in this study.

rhBMP-2/calcium phosphate matrix induces bone formation while limiting transient bone resorption in a nonhuman primate core defect model.

Background: Transient bone resorption limits the use of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge in metaphyseal bone. The purpose of the present study was to evaluate the efficacy of rhBMP-2/calcium phosphate matrix (CPM) to induce bone formation while limiting transient bone resorption in nonhuman primate core defects.

Methods: Metaphyseal core defects were created in eighteen cynomolgus monkeys.

Effect of bone morphogenetic protein 2 on tendon-to-bone healing in a canine flexor tendon model.

Tendon-to-bone healing is typically poor, with a high rate of repair-site rupture. Bone loss after tendon-to-bone repair may contribute to poor outcomes. Therefore, we hypothesized that the local application of the osteogenic growth factor bone morphogenetic protein 2 (BMP-2) would promote bone formation, leading to improved repair-site mechanical properties.

Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy.

Skeletal muscle atrophy can be a consequence of many diseases, environmental insults, inactivity, age, and injury. Atrophy is characterized by active degradation, removal of contractile proteins, and a reduction in muscle fiber size. Animal models have been extensively used to identify pathways that lead to atrophic conditions.

Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities.

Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn).

Regulation of gene expression in human tendinopathy.

Background: Chronic tendon injuries, also known as tendinopathies, are common among professional and recreational athletes. These injuries result in a significant amount of morbidity and health care expenditure, yet little is known about the molecular mechanisms leading to tendinopathy.

Methods: We have used histological evaluation and molecular profiling to determine gene expression changes in 23 human patients undergoing surgical procedures for the treatment of chronic tendinopathy.

Treatment with rhBMP12 or rhBMP13 increase the rate and the quality of rat Achilles tendon repair.

Tendon injuries that result in partial or complete tears often come from chronic, repetitive use, or from sudden trauma. In some cases, torn tendons can be repaired, but such repairs often fail to completely restore tendon function. We used global gene expression profiling and histological examination to study tendon repair to elucidate key molecular processes that regulate the rate and quality of tissue restoration.

rhBMP-2 induces transient bone resorption followed by bone formation in a nonhuman primate core-defect model.

Background: Bone resorption preceding bone formation has been reported following the administration of recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered in an absorbable collagen sponge (ACS) in metaphyseal bone. This study characterizes treatment with rhBMP-2/ACS in metaphyseal bone with use of a nonhuman primate core-defect model.

Methods: Unilateral proximal femoral core defects were treated with 360 microg of rhBMP-2/ACS or ACS alone or were left untreated in seven, five, and five adult male cynomolgus monkeys, respectively.

Tendon-selective genes identified from rat and human musculoskeletal tissues.

Mesenchymal stems cells have a demonstrated ability to differentiate into muscle, bone, and fat. Determining whether these same cells have the ability to differentiate into tendon-like fibroblasts has been hampered by the lack of specific tendon cell marker genes. In order to identify molecular markers of mature tendon, expression profiling was used to identify genes expressed in adult rat and human tendon tissue compared to other musculoskeletal tissues.

Clinical use of recombinant human bone morphogenic protein-2 in a whooping crane (Grus americana).

Objective: To report use of recombinant human bone morphogenetic protein-2 (rhBMP-2) as adjunctive therapy for treatment of a comminuted, open, proximal humeral fracture in an avian species.

Study Design: Clinical report.

Animals: A 3.

Mandibular reconstruction after gunshot trauma in a dog by use of recombinant human bone morphogenetic protein-2.

Case Description: A 6-year-old German Shorthaired Pointer was evaluated for possible reconstruction of a mandibular defect resulting from gunshot trauma.

Clinical Findings: A 5-cm defect of the right mandibular body was evident. A segment of the mandibular body was removed 9 weeks earlier because of severe contamination and comminution associated with gunshot trauma.

Effect of rhBMP-2 on tibial plateau fractures in a canine model.

This study was to determine the efficacy of recombinant human bone morphogenetic protien-2 (rhBMP-2)/calcium phosphate matrix (CPX) paste to accelerate healing in a canine articular fracture model with associated subchondral defect. rhBMP-2/CPX (BMP), CPX alone (CPX) or autogenous bone graft (ABG) was administered to a canine articular tibial plateau osteotomy with a subchondral defect in each of 21 female dogs. The unoperated contralateral limbs served as controls.

rhBMP-12 accelerates healing of rotator cuff repairs in a sheep model.

Background: The success rate of rotator cuff repairs is variable. This study was performed to evaluate the ability of recombinant human bone morphogenetic protein-12 (rhBMP-12), administered in several carriers, to accelerate healing in a sheep model of rotator cuff repair.

Methods: Local retention of tracer amounts of radiolabeled rhBMP-12, added to non-radiolabeled rhBMP-12 delivered in buffer, hyaluronan paste or sponges, or Type-I or Type-I/III collagen sponges was first evaluated with use of gamma scintigraphy in a pilot study of a rat intramuscular implant model.

Clinical application of recombinant human bone morphogenetic protein-2 in 4 dogs.

Objective: To describe outcome in dogs with insufficient bone healing treated with recombinant human bone morphogenetic protein-2 (rhBMP-2).

Study Design: Retrospective study.

Animals: Four dogs clinically affected with delayed union or nonunion bone healing.

rhBMP-2 delivered in a calcium phosphate cement accelerates bridging of critical-sized defects in rabbit radii.

Background: Treatment of segmental bone loss remains a challenge in skeletal repairs. This study was performed to evaluate the efficacy of the use of recombinant bone morphogenetic protein-2 (rhBMP-2) delivered in an injectable calcium phosphate cement (alpha bone substitute material [alpha-BSM]) to bridge critical-sized defects in the rabbit radius.

Methods: Unilateral 20-mm mid-diaphyseal defects were created in the radii of thirty-six skeletally mature New Zealand White rabbits.