Douglas C. Moore

Recombinant human platelet-derived growth factor-BB augmentation of new-bone formation in a rat model of distraction osteogenesis.

BACKGROUNDnDistraction osteogenesis creates a challenging bone-healing environment with protracted demand for cells of the osteoblast lineage. Platelet-derived growth factor-BB (PDGF-BB) is an osteoblast mitogen and chemotaxin that has been shown to accelerate and/or enhance bone-healing in several preclinical studies. The purpose of the present study was to determine whether recombinant human platelet-derived growth factor-BB (rhPDGF-BB) would have a similar effect on regenerate healing after distraction osteogenesis.nnnMETHODSnUnilateral 7-mm mid-diaphyseal femoral lengthening procedures were performed in eighty-three male Sprague-Dawley rats that were separated into five experimental groups. During the distraction period (Days 7 to 28), each animal received a weekly 50-microL injection of either sodium acetate buffer, bovine collagen dissolved in sodium acetate buffer, or one of three concentrations of rhPDGF-BB (100, 300, or 1000 microg/mL) into the distraction site. Animals from each group were killed on Days 35, 42, 49, 56, and 63. Healing was assessed with biweekly serial radiographs, micro-computed tomography of the explanted bones, and histologic analysis.nnnRESULTSnrhPDGF-BB treatment significantly increased new-bone formation at the midconsolidation time points (Days 42, 49, and 56) as well as the union rate. On Day 49 regenerate bone volume was significantly greater in each of the three rhPDGF-BB-treated groups than in the controls (p < 0.05, p = 0.0002, and p < 0.05 for the 100, 300, and 1000 microg/mL rhPDGF-BB groups, respectively), whereas on Day 42 regenerate bone volume was significantly greater in the 300 and 1000 microg/mL rhPDGF-BB groups than in the controls (p = 0.0002 and p < 0.05, respectively) and on Day 56 regenerate bone volume was significantly greater in the 100 and 300 microg/mL rhPDGF-BB groups than in the controls (p < 0.05 and p < 0.0001, respectively). The overall union rate was 40.4% (nineteen of forty-seven) in the rhPDGF-BB-treated animals, compared with 4.5% (one of twenty-two) in the controls (p = 0.01). The radiographic and histologic results were consistent with new-bone formation as quantified by micro-computed tomography, although they were less definitive.nnnCONCLUSIONSnThe administration of exogenous rhPDGF-BB into the distraction site during diaphyseal distraction enhanced bone-healing in a rat model of distraction osteogenesis as evidenced by both increased regenerate new-bone formation and a higher union rate.

Simulated radioscapholunate fusion alters carpal kinematics while preserving dart-thrower's motion.

PURPOSEnMidcarpal degeneration is well documented after radioscapholunate fusion. This study tested the hypothesis that radioscapholunate fusion alters the kinematic behavior of the remaining lunotriquetral and midcarpal joints, with specific focus on the dart-throwers motion.nnnMETHODSnSimulated radioscapholunate fusions were performed on 6 cadaveric wrists in an anatomically neutral posture. Two 0.060-in. carbon fiber pins were placed from proximal to distal across the radiolunate and radioscaphoid joints, respectively. The wrists were passively positioned in a custom jig toward a full range of motion along the orthogonal axes as well as oblique motions, with additional intermediate positions along the dart-throwers path. Using a computed tomography-based markerless bone registration technique, each carpal bones three-dimensional rotation was defined as a function of wrist flexion/extension from the pinned neutral position. Kinematic data was analyzed against data collected on the same wrist prior to fixation using hierarchical linear regression analysis and paired Students t-tests.nnnRESULTSnAfter simulated fusion, wrist motion was restricted to an average flexion-extension arc of 48 degrees , reduced from 77 degrees , and radial-ulnar deviation arc of 19 degrees , reduced from 33 degrees . The remaining motion was maximally preserved along the dart-throwers path from radial-extension toward ulnar-flexion. The simulated fusion significantly increased rotation through the scaphotrapezial joint, scaphocapitate joint, triquetrohamate joint, and lunotriquetral joint. For example, in the pinned wrist, the rotation of the hamate relative to the triquetrum increased 85%. Therefore, during every 10 degrees of total wrist motion, the hamate rotated an average of nearly 8 degrees relative to the triquetrum after pinning versus 4 degrees in the normal state.nnnCONCLUSIONSnSimulated radioscapholunate fusion altered midcarpal and lunotriquetral kinematics. The increased rotations across these remaining joints provide one potential explanation for midcarpal degeneration after radioscapholunate fusion. Additionally, this fusion model confirms the dart-throwers hypothesis, as wrist motion after simulated radioscapholunate fusion was primarily preserved from radial-extension toward ulnar-flexion.

In Vivo Kinematics of the Thumb Carpometacarpal Joint During Three Isometric Functional Tasks

BackgroundThe thumb carpometacarpal (CMC) joint is often affected by osteoarthritis—a mechanically mediated disease. Pathomechanics of the CMC joint, however, are not thoroughly understood due to a paucity of in vivo data.Questions/purposesWe documented normal, in vivo CMC joint kinematics during isometric functional tasks. We hypothesized there would be motion of the CMC joint during these tasks and that this motion would differ with sex and age group. We also sought to determine whether the rotations at the CMC joint were coupled and whether the trapezium moved with respect to the third metacarpal.MethodsForty-six asymptomatic subjects were CT-scanned in a neutral position and during three functional tasks (key pinch, jar grasp, jar twist), in an unloaded and a loaded position. Kinematics of the first metacarpal, third metacarpal, and the trapezium were then computed.ResultsSignificant motion was identified in the CMC joint during all tasks. Sex did not have an effect on CMC joint kinematics. Motion patterns differed with age group, but these differences were not systematic across the tasks. Rotation at the CMC joint was generally coupled and posture of the trapezium relative to the third metacarpal changed significantly with thumb position.ConclusionsThe healthy CMC joint is relatively stable during key pinch, jar grasp, and jar twist tasks, despite sex and age group.Clinical RelevanceOur findings indicate that directionally coupled motion patterns in the CMC joint, which lead to a specific loading profile, are similar in men and women. These patterns, in addition to other, nonkinematic influences, especially in the female population, may contribute to the pathomechanics of the osteoarthritic joint.

Attenuation of osteoarthritis via blockade of the SDF-1/CXCR4 signaling pathway

IntroductionThis study was performed to evaluate the attenuation of osteoarthritic (OA) pathogenesis via disruption of the stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling with AMD3100 in a guinea pig OA model.MethodsOA chondrocytes and cartilage explants were incubated with SDF-1, siRNA CXCR4, or anti-CXCR4 antibody before treatment with SDF-1. Matrix metalloproteases (MMPs) mRNA and protein levels were measured with real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The 35 9-month-old male Hartley guinea pigs (0.88 kg ± 0.21 kg) were divided into three groups: AMD-treated group (n = 13); OA group (n = 11); and sham group (n = 11). At 3 months after treatment, knee joints, synovial fluid, and serum were collected for histologic and biochemical analysis. The severity of cartilage damage was assessed by using the modified Mankin score. The levels of SDF-1, glycosaminoglycans (GAGs), MMP-1, MMP-13, and interleukin-1 (IL-1β) were quantified with ELISA.ResultsSDF-1 infiltrated cartilage and decreased proteoglycan staining. Increased glycosaminoglycans and MMP-13 activity were found in the culture media in response to SDF-1 treatment. Disrupting the interaction between SDF-1 and CXCR4 with siRNA CXCR4 or CXCR4 antibody attenuated the effect of SDF-1. Safranin-O staining revealed less cartilage damage in the AMD3100-treated animals with the lowest Mankin score compared with the control animals. The levels of SDF-1, GAG, MMP1, MMP-13, and IL-1β were much lower in the synovial fluid of the AMD3100 group than in that of control group.ConclusionsThe binding of SDF-1 to CXCR4 induces OA cartilage degeneration. The catabolic processes can be disrupted by pharmacologic blockade of SDF-1/CXCR4 signaling. Together, these findings raise the possibility that disruption of the SDF-1/CXCR4 signaling can be used as a therapeutic approach to attenuate cartilage degeneration.

The morphology of the thumb carpometacarpal joint does not differ between men and women, but changes with aging and early osteoarthritis

The high prevalence of thumb carpometacarpal (CMC) joint osteoarthritis (OA) in women has been previously linked to the articular morphology of the trapezium. Studies report conflicting results on how the articular shapes of male and female trapezia compare to one another, however, mainly because their findings are based on data from older cadaveric specimens. The purpose of this in vivo study was to dissociate the effect of sex from that of aging and early OA by using cohorts of healthy young and healthy older subjects, as well as patients with early stage OA. Computed tomography scans from 68 healthy subjects and 87 arthritic subjects were used to obtain 3-D bone models. The trapezial and metacarpal articular surfaces were manually delineated on scaled bone models and compared between sex, age, and health groups by using polar histograms of curvature and average curvatures. We found no sex-related differences, but significant age-group and health-group differences, in the articular surfaces of both bones. Older healthy subjects had higher curvature in the concave and lower curvature in the convex directions of both the trapezial and metacarpal saddles than healthy young subjects. Subjects with early OA had significantly different metacarpal and trapezial articular shapes from healthy subjects of the same age group. These findings suggest that aging and OA affect the articular shape of the CMC joint, but that, in contrast to previously held beliefs, inherent sex differences are not responsible for the higher incidence of CMC OA in women.

Reduced limb length and worsened osteoarthritis in adult mice after genetic inhibition of p38 MAP kinase activity in cartilage

OBJECTIVEnMAP kinase p38 is part of an intracellular signaling pathway activated by environmental stress and inflammatory factors. Since in vitro studies show that inhibiting p38 activity leads to a reduction in the release of degenerative metalloproteinase from chondrocytes, we speculated that inactivation of p38 in vivo may be chondroprotective. To test this hypothesis, we examined the morphology of adult mice that express a dominant-negative (DN) p38 MAPK transgene in a cartilage-specific manner.nnnMETHODSnThe in vivo effects of the genetic inhibition of p38 MAPK activity in cartilage were investigated in 1-year-old heterozygous DN p38-transgenic mice (n = 10) using morphologic measurements, microfocal computed tomography scanning, biomechanical testing, and histologic analysis. Results were compared with those in wild-type (WT) littermates (n = 9).nnnRESULTSnAdult DN p38 MAPK+/- -transgenic mice exhibited 50% p38 MAPK activity in articular chondrocytes as compared with WT mice. They were significantly shorter in overall body length as well as in the femur and tibia lengths. There were no differences in bone material or mechanical properties between the transgenic and WT mice. Surprisingly, the transgenic mice had higher grades of osteoarthritis of the knee joint.nnnCONCLUSIONnGenetic inhibition of p38 MAPK activity in cartilage results in shortened limb length and defects in the articular cartilage of the knee joints of adult mice. Our findings demonstrate that chronic life-long reduction of p38 MAPK activity may be harmful to joint health and suggest that the timing of p38 inhibition for chondroprotection in vivo is an important variable that warrants further investigation.

Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist.

Background: Matrilin-3-deficient mice exhibit increased chondrocyte hypertrophy and early osteoarthritis. Results: Matrilin-3 binds bone morphogenetic factor-2 (BMP-2) and inhibits downstream BMP-2 signaling. Conclusion: The biological function of matrilin-3 involves modulating BMP-2 pathway activity. Significance: This is the first demonstration that matrilin-3 regulates chondrocyte hypertrophy as a BMP-2 antagonist in cartilage. Increased chondrocyte hypertrophy is often associated with cartilage joint degeneration in human osteoarthritis patients. Matrilin-3 knock-out (Matn3 KO) mice exhibit these features. However, the underlying mechanism is unknown. In this study, we sought a molecular explanation for increased chondrocyte hypertrophy in the mice prone to cartilage degeneration. We analyzed the effects of Matn3 on chondrocyte hypertrophy and bone morphogenetic protein (Bmp) signaling by quantifying the hypertrophic marker collagen type X (Col X) gene expression and Smad1 activity in Matn3 KO mice in vivo and in Matn3-overexpressing chondrocytes in vitro. The effect of Matn3 and its specific domains on BMP activity were quantified by Col X promoter activity containing the Bmp-responsive element. Binding of MATN3 with BMP-2 was determined by immunoprecipitation, solid phase binding, and surface plasmon resonance assays. In Matn3 KO mice, Smad1 activity was increased more in growth plate chondrocytes than in wild-type mice. Conversely, Matn3 overexpression in hypertrophic chondrocytes led to inhibition of Bmp-2-stimulated, BMP-responsive element-dependent Col X expression and Smad1 activity. MATN3 bound BMP-2 in a dose-dependent manner. Multiple epidermal growth factor (EGF)-like domains clustered together by the coiled coil of Matn3 is required for Smad1 inhibition. Hence, as a novel BMP-2-binding protein and antagonist in the cartilage extracellular matrix, MATN3 may have the inherent ability to inhibit premature chondrocyte hypertrophy by suppressing BMP-2/Smad1 activity.

A thumb carpometacarpal joint coordinate system based on articular surface geometry

The thumb carpometacarpal (CMC) joint is a saddle-shaped articulation whose in vivo kinematics can be explored more accurately with computed tomography (CT) imaging methods than with previously used skin-based marker systems. These CT-based methods permit a detailed analysis of the morphology of the joint, and thus the prominent saddle geometry can be used to define a coordinate system that is inherently aligned with the primary directions of motion at the joint. The purpose of this study was to develop a CMC joint coordinate systems that is based on the computed principal directions of curvature on the trapezium and the first metacarpal. We evaluated the new coordinate system using bone surface models segmented from the CT scans of 24 healthy subjects. An analysis of sensitivity to the manual selection of articular surfaces resulted in mean orientation differences of 0.7±0.7° and mean location differences of 0.2±0.1mm. Inter-subject variability, which mostly emanates from anatomical differences, was evaluated with whole bone registration and resulted in mean orientation differences of 3.1±2.7° and mean location differences of 0.9±0.5mm. The proposed joint coordinate system addresses concerns of repeatability associated with bony landmark identification and provides a robust platform for describing the complex kinematics of the CMC joint.

In vivo recruitment patterns in the anterior oblique and dorsoradial ligaments of the first carpometacarpal joint

The anterior oblique ligament (AOL) and the dorsoradial ligament (DRL) are both regarded as mechanical stabilizers of the thumb carpometacarpal (CMC) joint, which in older women is often affected by osteoarthritis. Inferences on the potential relationship of these ligaments to joint pathomechanics are based on clinical experience and studies of cadaveric tissue, but their functions has been studied sparsely in vivo. The purpose of this study was to gain insight into the functions of the AOL and DRL using in vivo joint kinematics data. The thumbs of 44 healthy subjects were imaged with a clinical computed tomography scanner in functional-task and thumb range-of-motion positions. The origins and insertion sites of the AOL and the DRL were identified on the three-dimensional bone models and each ligament was modeled as a set of three fibers whose lengths were the minimum distances between insertion sites. Ligament recruitment, which represented ligament length as a percentage of the maximum length across the scanned positions, was computed for each position and related to joint posture. Mean AOL recruitment was lower than 91% across the CMC range of motion, whereas mean DRL recruitment was generally higher than 91% in abduction and flexion. Under the assumption that ligaments do not strain by more than 10% physiologically, our findings of mean ligament recruitments across the CMC range of motion indicate that the AOL is likely slack during most physiological positions, whereas the DRL may be taut and therefore support the joint in positions of CMC joint abduction and flexion.

The Envelope of Physiological Motion of the First Carpometacarpal Joint

Much of the hands functional capacity is due to the versatility of the motions at the thumb carpometacarpal (CMC) joint, which are presently incompletely defined. The aim of this study was to develop a mathematical model to completely describe the envelope of physiological motion of the thumb CMC joint and then to examine if there were differences in the kinematic envelope between women and men. In vivo kinematics of the first metacarpal with respect to the trapezium were computed from computed tomography (CT) volume images of 44 subjects (20M, 24F, 40.3u2009±u200917.7u2009yr) with no signs of CMC joint pathology. Kinematics of the first metacarpal were described with respect to the trapezium using helical axis of motion (HAM) variables and then modeled with discrete Fourier analysis. Each HAM variable was fit in a cyclic domain as a function of screw axis orientation in the trapezial articular plane; the RMSE of the fits was 14.5u2009deg, 1.4u2009mm, and 0.8u2009mm for the elevation, location, and translation, respectively. After normalizing for the larger bone size in men, no differences in the kinematic variables between sexes could be identified. Analysis of the kinematic data also revealed notable coupling of the primary rotations of the thumb with translation and internal and external rotations. This study advances our basic understanding of thumb CMC joint function and provides a complete description of the CMC joint for incorporation into future models of hand function. From a clinical perspective, our findings provide a basis for evaluating CMC pathology, especially the mechanically mediated aspects of osteoarthritis (OA), and should be used to inform artificial joint design, where accurate replication of kinematics is essential for long-term success.