Objective:This study evaluated the Yucatan minipig (YMP) as a translational large-animal model of wrist osteoarthritis (OA) following ligament injury (LI) or small bone replacement (SBR) in a 12-week in vivo study. Method:Eight YMPs were assigned to LI or SBR groups (n = 4/group). Gait data were collected preoperatively and at 3, 6, 9, and 12 weeks postoperatively. Ratios of surgical to contralateral limbs were calculated for maximum force, impulse, stance time, and stride velocity and compared within and between groups. At study completion, bilateral forelimbs were analyzed to quantify osteophyte volume, joint space, and cartilage health using OARSI histological scoring. Generalized estimating equations were used to evaluate differences in the outcome metrics between the LI and SBR groups. Results:The SBR group demonstrated significant gait asymmetry at week 3, with reduced maximum force, impulse, and stance time relative to preoperative values (p < 0.05), followed by partial recovery. Compared to the LI group whose symmetry was consistent over time, the SBR group exhibited greater gait asymmetry (p < 0.05) at all postoperative timepoints, while stride velocity remained unchanged. Osteophyte volume was greater in SBR than LI for seven of twelve bones (p < 0.05), whereas joint space did not differ among limbs or groups. Histological analysis revealed significantly higher total OARSI scores in SBR operated limbs compared to contralateral limbs, with greater cartilage degeneration than LI (p < 0.05). Conclusion:These findings characterize changes in gait and joint health that demonstrate the feasibility of the YMP as a translational preclinical model of the human wrist for assessing OA progression and SBR.

Hemiarthroplasty addresses joint damage confined to one side, preserving native cartilage and bone, but accelerated degeneration of the opposing cartilage can compromise outcomes. This systematic review should clarify whether coefficient of friction (COF) reliably predicts cartilage wear when evaluating hemiarthroplasty bearing materials (HBMs). Thirty in vitro studies reporting both outcomes were identified. Data were extracted on COF, wear, and testing parameters, and wear was standardized using a 0–4 rubric to enable cross-study comparison. Three analytical approaches were applied: linear model fits, Pearson’s correlations, and predictive modeling. Reported COFs increased significantly with testing time, while contact stress and sliding velocity showed variable associations with COF. Predictive models for cobalt–chromium (CoCr), the most studied HBM, showed moderate fit, suggesting that mechanical parameters explain only part of COF variability. For wear, linear models showed poor fit with COF, but correlations indicated positive associations with contact stress. Inconsistent effects of velocity and distance were found. Predictive models explained little variability. Together, these findings suggest that outcomes are strongly influenced by testing conditions, lubricants, and HBM selection, and COF alone is an unreliable predictor of cartilage wear in an experimental setting.

The present study aims to determine if morphological differences of the scaphoid, trapezoid, and second metacarpal are associated with thumb osteoarthritis by comparing three-dimensional bone models of healthy controls and osteoarthritis patients. Fifty-eight patients with moderate to severe thumb osteoarthritis (modified Eaton ≥ II) and 35 healthy controls from a larger completed investigation were examined. To quantify morphological variations, a statistical shape model was created that classified binary with respect to the Eaton grading system: non-osteoarthritis or moderate/severe osteoarthritis (II-IV). Three-dimensional surface models based on computed tomography images from the scaphoid, trapezoid, and second metacarpal were used to "train" the statistical shape model and yielded features that best explain variation within the three bones: the principal components These principal components were tested for significant differences between patient and control group. Additionally, a statistical shape model entailing all three bones was created. For the second metacarpal, only a single principal component was significantly associated with osteoarthritis (p = 0.035). The combined model utilizing all three bones, however, showed that with using one principal component of each of the bones, we could classify a sample as moderate/severe trapeziometacarpal osteoarthritis with an accuracy of 0.77. No individual shape components of the scaphoid or trapezoid significantly correlated to osteoarthritis. This study affirms that basilar thumb osteoarthritis is not limited to the trapeziometacarpal joint. Future studies investigating surrounding bones and joints as contributors to disease occurrence or progression will provide a more holistic insight into the prevention, diagnostic, and treatment of thumb osteoarthritis.

Thumb motion is a key outcome metric for assessing disease progression or treatment efficacy. A literature review found nearly 25 % of recent papers incorrectly described their motion measurements as those of the first carpometacarpal (CMC) joint, when in fact their technology was only capable of measuring thumb motion. The aim of this manuscript is to clarify the importance of the accurate terminology and to rigorously examine the potential error by comparing thumb motion and CMC joint motion. Computed tomography (CT) images from 46 healthy subjects were analyzed using 3D markerless bone registration techniques to compute thumb rotation (first metacarpal (MC1) relative to the radius) and CMC joint rotation (MC1 relative to trapezium). We found thumb rotation was a poor measure of CMC joint rotation. For example, at thumb rotations of 20°, the true CMC joint rotations ranged from 3° to 30°. On average, thumb rotation over predicted CMC rotation by approximately 10°, with 95 % Limits of Agreement ranging from 30° (over estimating CMC joint motion) to -11° (underestimating CMC joint motion). Importantly, the character of the data demonstrated that CMC motion cannot be predicted from thumb motion. 3D CMC joint motion can only be assessed with skeletal imaging technologies; goniometers and skin-based markers can, at best, only measure thumb motion. Referring to goniometer and skin marker measurements as CMC joint motion is incorrect. It is critical that investigators be precise in their reporting of thumb motion versus CMC joint motion, especially when reporting interventions for thumb pathologies.

Hemiarthroplasty is commonly used to treat damage localized to one side of a synovial joint, maximally preserving the patient's opposing healthy bone and cartilage; however, challenges remain due to accelerated wear of the cartilage articulating with the implant surface. This scoping review summarized investigations of hemiarthroplasty bearing materials (HBMs) utilizing animal models. The review focused on HBMs tested, animal models used, duration of animal survival, and outcome assessments (e.g., gait analysis, image analysis, histological staining, and cartilage scoring). The initial search was designed to broadly capture all studies evaluating HBMs articulating against articular cartilage. A total of 1798 studies were identified, which after screening yielded 72 that met the inclusion criteria. Of these, 24 were classified as in vivo and were included in this review. The HBMs evaluated included metals (63%), hard and soft polymers (33%), ceramics (17%), and synthetic carbons (17%). HBMs were predominantly studied in canines (46%), rabbits (25%), and sheep (21%), with survival durations from 2 to 104 weeks. Outcome assessment of cartilage wear varied across studies and histological staining was performed in all studies with the most common stains being Safranin-O (58%) and Hematoxylin and Eosin (54%). Commonly used cartilage scoring systems were Mankin and Modified Mankin (38%); however, among all studies, scales and sub-categories for scoring criteria varied drastically. While similarities were identified with respect to HBMs, animal models, and some outcome measures, the diversity of testing methodologies and lack of comparative evaluations limited the ability to identify the best practice for evaluating HBM performance.

Hemiarthroplasty is used to treat joint damage confined to one side, aiming to preserve the remaining healthy cartilage and bone while addressing conditions like femur fractures and osteonecrosis; however, challenges persist due to cartilage wear and inconsistent clinical outcomes. This scoping review evaluates in vitro studies on hemiarthroplasty bearing materials (HBM), focusing on the HBM tested, cartilage specimens, experimental setups, outcome variables, and the comparability of results. Of 1798 identified studies, 72 met the inclusion criteria, with 48 classified as in vitro. HBMs tested included metals (42%) and soft polymers (30%) and 45% of studies utilized multiple distinct HBMs. Cartilage specimens were predominantly bovine (65%), mostly from the tibial-femoral joint (69%). The two most common experimental set ups were tribometers (75%) and simulators (25%) both using commercial and custom-built rigs. Tribometer configurations included pin-on-disc and pin-on-plate models and simulators highlighted ball-on-joint set ups. Tribometer motions included linear reciprocating (62%) or multidirectional reciprocating (24%). Input parameters included contact stress (8.8 kPa to 23.3 MPa, mean 2.1 MPa), velocity (0.5-100 mm/s, mean 16.46 mm/s), testing duration (0.03-33.8 h, mean 5.4 h), and distance (5.4 cm to 9000 m, mean 393 m). Simulators used inputs of loads ranging from 25 N to 1.5 kN, 500 to 500,000 cycles and a variety of flexion-extension profiles together with secondary motions. Lubricants were mostly bovine calf serum (38%) and saline-based solutions (21%). Outcome variables mainly included coefficient of friction and damage to cartilage and/or HBM, but the methods to assess these outputs varied. Methodological differences and inconsistent reporting of outcomes limited the ability to draw firm conclusions about the relative performance of HBMs.

Tracking skeletal joint kinematics in vivo with biplane videoradiography (BVR) can rigorously address a range of important questions in musculoskeletal research. Here we report on SlicerAutoscoperM (SAM), an upgrade of the markerless tracking software (Autoscoper) and its migration into the established computing environment of 3DSlicer and addition of a comprehensive pre-processing module to provide a standardized workflow. We present the accuracy and agreement in tracking four skeletal joints by four research groups. Accuracy was assessed by comparing marker-generated and SAM kinematics for bones of the foot, knee, shoulder, and wrist. Bland-Altman analyses quantified bias (mean error) and limits of agreement (LOA). Tracking accuracy was robust for all joints. In the foot, mean error (bias) was less than 0.5° (1.8°) and 0.8 mm (3.1 mm). In the knee, mean error was less than 1.0° (1.5°) and 0.4 mm (0.8 mm). In the shoulder, mean translational error for both the humerus and scapula was less than 0.2 mm (0.7 mm). Rotational error was highest in Roll and Pitch for the humerus, 1.9° (4.8°) and 1.7° (4.6°), respectively, and Yaw was 0.3° (2.1°). The scapula rotational bias was less than 0.2° (0.7°). In the wrist, the error was less than 0.05° (1.2°) and 0.5 mm (1.2 mm). Our data demonstrate that SAM is an accurate image-based skeletal motion tracking tool. With broad adoption, SAM will promote collaboration, simplify the harmonization of methods between study sites for large multi-center research studies, lower the entry bar for early-stage investigators, and facilitate translations toward clinical use.

Understanding the loads that occur across musculoskeletal joints is critical to advancing our understanding of joint function and pathology, implant design and testing, as well as model verification. Substantial work in these areas has occurred in the hip and knee but has not yet been undertaken in smaller joints, such as those in the wrist. The thumb carpometacarpal (CMC) joint is a uniquely human articulation that is also a common site of osteoarthritis with unknown etiology. We present two potential designs for an instrumented trapezium implant and compare approaches to load calibration. Two instrumented trapezia designs were prototyped using strain gauge technology: Tube and Diaphragm. The Tube design is a well-established structure for sensing loads while the Diaphragm is novel. Each design was affixed to a 6-DOF load cell that was used as the reference. Loads were applied manually, and two calibration methods, supervised neural network (DEEP) and matrix algebra (MAT), were implemented. Bland-Altman 95% confidence interval for the limits of agreement (95% CI LOA) was used to assess accuracy. Overall, the DEEP calibration decreased 95% CI LOA compared with the MAT approach for both designs. The Diaphragm design outperformed the Tube design in measuring the primary load vector (joint compression). Importantly, the Diaphragm design permits the hermetic encapsulation of all electronics, which is not possible with the Tube design, given the small size of the trapezium. Substantial work remains before this device can be approved for implantation, but this work lays the foundation for further device development that will be required.

Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4(+) AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan(+) pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.

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BACKGROUND:Measurable changes in patients with progression of thumb carpometacarpal (CMC) osteoarthritis (OA) include joint space narrowing, osteophyte formation, subluxation, and adjacent-tissue changes. Subluxation, an indication of mechanical instability, is postulated as an early biomechanical indicator of progressing CMC OA. Various radiographic views and hand postures have been proposed to best assess CMC subluxation, but 3D measurements derived from CT images serve as the optimal metric. However, we do not know which thumb pose yields subluxation that most indicates OA progression.QUESTIONS/PURPOSES:Using osteophyte volume as a quantitative measure of OA progression, we asked: (1) Does dorsal subluxation vary by thumb pose, time, and disease severity in patients with thumb CMC OA? (2) In which thumb pose(s) does dorsal subluxation most differentiate patients with stable CMC OA from those with progressing CMC OA? (3) In those poses, what values of dorsal subluxation indicate a high likelihood of CMC OA progression?METHODS:Between 2011 and 2014, 743 patients were seen at our institutions for trapeziometacarpal pain. We considered individuals who were between the ages of 45 and 75 years, had tenderness to palpation or a positive grind test result, and had modified Eaton Stage 0 or 1 radiographic thumb CMC OA as potentially eligible for enrollment. Based on these criteria, 109 patients were eligible. Of the eligible patients, 19 were excluded because of a lack of interest in study participation, and another four were lost before the minimum study follow-up or had incomplete datasets, leaving 86 (43 female patients with a mean age of 53 ± 6 years and 43 male patients with a mean age of 60 ± 7 years) patients for analysis. Twenty-five asymptomatic participants (controls) aged 45 to 75 years were also prospectively recruited to participate in this study. Inclusion criteria for controls included an absence of thumb pain and no evidence of CMC OA during clinical examination. Of the 25 recruited controls, three were lost to follow-up, leaving 22 for analysis (13 female patients with a mean age of 55 ± 7 years and nine male patients with a mean age of 58 ± 9 years). Over the 6-year study period, CT images were acquired of patients and controls in 11 thumb poses: neutral, adduction, abduction, flexion, extension, grasp, jar, pinch, grasp loaded, jar loaded, and pinch loaded. CT images were acquired at enrollment (Year 0) and Years 1.5, 3, 4.5, and 6 for patients and at Years 0 and 6 for controls. From the CT images, bone models of the first metacarpal (MC1) and trapezium were segmented, and coordinate systems were calculated from their CMC articular surfaces. The volar-dorsal location of the MC1 relative to the trapezium was computed and normalized for bone size. Patients were categorized into stable OA and progressing OA subgroups based on trapezial osteophyte volume. MC1 volar-dorsal location was analyzed by thumb pose, time, and disease severity using linear mixed-effects models. Data are reported as the mean and 95% confidence interval. Differences in volar-dorsal location at enrollment and rate of migration during the study were analyzed for each thumb pose by group (control, stable OA, and progressing OA). A receiver operating characteristic curve analysis of MC1 location was used to identify thumb poses that differentiated patients whose OA was stable from those whose OA was progressing. The Youden J statistic was used to determine optimized cutoff values of subluxation from those poses to be tested as indicators of OA progression. Sensitivity, specificity, negative predictive values, and positive predictive values were calculated to assess the performance of pose-specific cutoff values of MC1 locations as indicators of progressing OA.RESULTS:In flexion, the MC1 locations were volar to the joint center in patients with stable OA (mean -6.2% [95% CI -8.8% to -3.6%]) and controls (mean -6.1% [95% CI -8.9% to -3.2%]), while patients with progressing OA exhibited dorsal subluxation (mean 5.0% [95% CI 1.3% to 8.6%]; p < 0.001). The pose associated with the most rapid MC1 dorsal subluxation in the progressing OA group was thumb flexion (mean 3.2% [95% CI 2.5% to 3.9%] increase per year). In contrast, the MC1 migrated dorsally much slower in the stable OA group (p < 0.001), at only a mean of 0.1% (95% CI -0.4% to 0.6%) per year. A cutoff value of 1.5% for the volar MC1 position during flexion at enrollment (C-statistic: 0.70) was a moderate indicator of OA progression, with a high positive predictive value (0.80) but low negative predictive value (0.54). Positive and negative predictive values of subluxation rate in flexion (2.1% per year) were high (0.81 and 0.81, respectively). The metric that most indicated a high likelihood of OA progression (sensitivity 0.96, negative predictive value 0.89) was a dual cutoff that combined the subluxation rate in flexion (2.1% per year) with that of loaded pinch (1.2% per year).CONCLUSION:In the thumb flexion pose, only the progressing OA group exhibited MC1 dorsal subluxation. The MC1 location cutoff value for progression in flexion was 1.5% volar to the trapezium , which suggests that dorsal subluxation of any amount in this pose indicates a high likelihood of thumb CMC OA progression. However, volar MC1 location in flexion alone was not sufficient to rule out progression. The availability of longitudinal data improved our ability to identify patients whose disease will likely remain stable. In patients whose MC1 location during flexion changed < 2.1% per year and whose MC1 location during pinch loading changed < 1.2% per year, the confidence that their disease would remain stable throughout the 6-year study period was very high. These cutoff rates were a lower limit, and any patients whose dorsal subluxation advanced faster than 2% to 1% per year in their respective hand poses, were highly likely to experience progressive disease.CLINICAL RELEVANCE:Our findings suggest that in patients with early signs of CMC OA, nonoperative interventions aimed to reduce further dorsal subluxation or operative treatments that spare the trapezium and limit subluxation may be effective. It remains to be determined whether our subluxation metrics can be rigorously computed from more widely available technologies, such as plain radiography or ultrasound.

Osteoarthritis (OA) at the base of the thumb is a highly prevalent disease that presents with significant impairment in performing activities of daily living due to pain and weakness and is generally associated with decreases in range of motion (ROM). However, the correlation between changes in motion of the first carpometacarpal joint (CMC) or overall thumb motion with OA progression has not been previously examined. The aim of this study was to quantify changes in ROM over time in a six-year observational study of early CMC OA progression. We measured ROM with two methods: CT image-based CMC motion and standardized goniometer measurements of thumb motion. We recruited 86 patients who presented with early-stage thumb CMC OA and 22 age-matched controls. Patient assessments were performed at 0, 1.5, 3, 4.5, and 6 years and control assessments at 0 and 6 years. OA patients were categorized into two subgroups, Stable OA and Progressing OA, based upon osteophyte volume and growth rate. CMC flexion, extension, abduction, and adduction ROM decreased within the study period in the Progressing OA group, but not in the Stable OA or Healthy Control groups. Thumb flexion and abduction ROM did not change in any group. Thumb extension ROM decreased in similar deghrees in all three groups. This study highlights potential challenges with measuring thumb motion as opposed to measuring motion at specific joints using CT image-based methodologies or similar technologies. The mechanism associated with the decreased CMC ROM with disease progression was not identified in this study.

BACKGROUND:Thumb carpometacarpal osteoarthritis is characterized by osteophyte growth and changes in the curvature of the articular surfaces of the trapezium and first metacarpal. The aim of this longitudinal study was to quantify in-vivo bone morphology changes with osteoarthritis progression. METHODS:The study analyzed an observational dataset of 86 subjects with early thumb osteoarthritis and 22 age-matched asymptomatic controls. CT scans of subjects' affected hands were acquired at enrollment (year 0), and at 1.5, 3, 4.5, and 6-year follow-up visits. Osteoarthritic subjects were classified into stable and progressive groups, as defined by osteophyte volume and the rate of osteophyte growth. Trapezium height, width, and volar facet recession, along with first metacarpal volar beak recession and recession angle, were quantified. FINDINGS:Mean trapezium width increased 12% over six years in the progressive osteoarthritis group. Trapezium volar recession of the progressive osteoarthritis group was significantly greater than stable at enrollment (P < 0.0001) and year 6 (P < 0.0001). The first metacarpal volar beak of the progressive osteoarthritis group recessed significantly faster than stable (P = 0.0004) and control (P = 0.0003). In year 6, volar beak surfaces in subjects with progressive osteoarthritis were flatter with reduced curvature, measuring -8.7 ± 4.0 degrees, compared to the stable osteoarthritis (P < 0.0001) and control groups (P = 0.0003), which maintained nominal curvatures, measuring 0.7 ± 2.5 and 0.2 ± 3.2 degrees, respectively. INTERPRETATION:Our results demonstrate significant recession and reduction in the angle of the first metacarpal volar beak in progressive osteoarthritis. Flattening of the first metacarpal volar beak may have important associations with carpometacarpal joint contact and loading migrations, further propagating osteophyte formation and bony remodeling. This work highlights the volar beak of the first metacarpal as a region of morphology change with disease.

PURPOSE:Internal consistency, construct, and criterion validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) v1.2 were evaluated in patients with early-stage carpometacarpal (CMC) osteoarthritis (OA). We hypothesized that in patients with early CMC OA, PROMIS UE scores would: (1) be lower than those in asymptomatic controls; (2) correlate with established patient-reported outcomes; (3) correlate with pinch and grip strengths; and (4) not correlate with radiographic disease progression. METHODS:Patients with early CMC OA (modified Eaton stage 0 or 1) and matched asymptomatic control patients completed the PROMIS UE, Australian and Canadian Osteoarthritis Hand Index, and Patient-Rated Wrist-Hand Evaluation at 2 time points. The PROMIS UE's internal consistency was evaluated by Cronbach's alpha, construct validity by Spearman correlation coefficients among the patient-reported outcome measures, and criterion validity using measures of strength. A floor or ceiling effect was indicated if more than 15% of patients achieved the lowest or highest possible score. RESULTS:The PROMIS UE had high internal consistency. Patients with early CMC OA had a lower score than healthy controls (average, 42 vs 54, respectively). We observed moderate to high correlations between the PROMIS UEv1.2, Australian and Canadian Osteoarthritis Hand Index, and Patient-Rated Wrist-Hand Evaluation and good criterion validity when compared to key pinch and grip strengths. The PROMIS UE did not correlate to radiographic disease severity. CONCLUSIONS:The PROMIS UE had a high correlation with Australian and Canadian Osteoarthritis Hand Index and a moderate correlation with Patient-Rated Wrist-Hand Evaluation. The PROMIS UE had high internal consistency and good criterion validity. CLINICAL RELEVANCE:The PROMIS UE is a valid assessment for disability in patients with early CMC OA and can serve as a clinical adjunct to an outcome assessment.

Optical motion capture (OMC) systems are commonly used to capture in-vivo three-dimensional joint kinematics. However, the skin-based markers may not reflect the underlying bone movement, a source of error known as soft tissue artifact (STA). This study examined STA during wrist motion by evaluating the agreement between OMC and biplanar videoradiography (BVR). Nine subjects completed 7 different wrist motion tasks: doorknob rotation to capture supination and pronation, radial-ulnar deviation, flex-ion-extension, circumduction, hammering, and pitcher pouring. BVR and OMC captured the motion simultaneously. Wrist kinematics were quantified using helical motion parameters of rotation and trans-lation, and Bland-Altman analysis quantified the mean difference (bias) and 95% limit of agreement (LOA). The rotational bias of doorknob pronation, a median bias of-4.9 degrees, was significantly larger than the flexion-extension (0.7 degrees, p < 0.05) and radial-ulnar deviation (1.8 degrees, p < 0.01) tasks. The rotational LOA range was significantly smaller in the flexion-extension task (5.9 degrees) compared to pitcher (11.6 degrees, p < 0.05) and doorknob pronation (17.9 degrees, p < 0.05) tasks. The translation bias did not differ between tasks. The translation LOA range was significantly larger in circumduction (9.8 degrees) compared to the radial-ulnar deviation (6.3 degrees, p < 0.05) and pitcher (3.4 degrees, p < 0.05) tasks. While OMC technology has a wide-range of successful applications, we demonstrated it has relatively poor agreement with BVR in tracking wrist motion, and that the agreement depends on the nature and direction of wrist motion. (c) 2021 Elsevier Ltd. All rights reserved.

The protein tyrosine phosphatase SHP2, encoded by PTPN11, is ubiquitously expressed and essential for the development and/or maintenance of multiple tissues and organs. SHP2 is involved in gastrointestinal (GI) epithelium development and homeostasis, but the underlying mechanisms remain elusive. While studying SHP2's role in skeletal development, we made osteoblast-specific SHP2 deficient mice using Osterix (Osx)-Cre as a driver to excise Ptpn11 floxed alleles. Phenotypic characterization of these SHP2 mutants unexpectedly revealed a critical role of SHP2 in GI biology. Mice lacking SHP2 in Osx+ cells developed a fatal GI pathology with dramatic villus hypoplasia. OSTERIX, an OB-specific zinc finger-containing transcription factor is for the first time found to be expressed in GI crypt cells, and SHP2 expression in the crypt Osx+ cells is critical for self-renewal and proliferation. Further, immunostaining revealed the colocalization of OSTERIX with OLFM4 and LGR5, two bona fide GI stem cell markers, at the crypt cells. Furthermore, OSTERIX expression is found to be associated with GI malignancies. Knockdown of SHP2 expression had no apparent influence on the relative numbers of enterocytes, goblet cells or Paneth cells. Given SHP2's key regulatory role in OB differentiation, our studies suggest that OSTERIX and SHP2 are indispensable for gut homeostasis, analogous to SOX9's dual role as a master regulator of cartilage and an important regulator of crypt stem cell biology. Our findings also provide a foundation for new avenues of inquiry into GI stem cell biology and of OSTERIX's therapeutic and diagnostic potential.

Abstract Purpose There is a lack of quantitative research that describes the alignment and, more importantly, the effects of malalignment on total wrist arthroplasty (TWA). The main goal of this pilot study was to assess the alignment of TWA components in radiographic images and compare them with measures computed by three-dimensional analysis. Using these measures, we then determined if malalignment is associated with range of motion (ROM) or clinical outcomes (PRWHE, PROMIS, QuickDash, and grip strength). Methods Six osteoarthritic patients with a single type of TWA were recruited. Radiographic images, computed tomography images, and clinical outcomes of the wrists were recorded. Using posteroanterior and lateral radiographs, alignment measurements were defined for the radial and carpal components. Radiographic measurements were validated with models reconstructed from computed tomography images using Bland–Altman analysis. Biplanar videoradiography (<1mm and <1 degree accuracy) was used to capture and compute ROM of the TWA components. Linear regression assessed the associations between alignment and outcomes. Results Radiographic measures had a 95% limit-of-agreement (mean difference ±  1.96 × SD) of 3 degrees and 3mm with three-dimensional values, except for the measures of the carpal component in the lateral view. In our small cohort, wrist flexion–extension and radial–ulnar deviation were correlated with volar–dorsal tilt and volar–dorsal offset of the radial component and demonstrated a ROM increase of 3.7 and 1.6 degrees per degree increase in volar tilt, and 10.8 and 4.2 degrees per every millimeter increase in volar offset. The carpal component's higher volar tilt was also associated with improvements in patient-reported pain. Conclusions We determined metrics describing the alignment of TWA, and found the volar tilt and volar offset of the radial component could potentially influence the replaced wrist's ROM. Clinical Relevance TWA component alignment can be measured reliably in radiographs, and may be associated with clinical outcomes. Future studies must evaluate its role in a larger cohort.

Accurate measurement of skeletal kinematics in vivo is essential for understanding normal joint function, the influence of pathology, disease progression, and the effects of treatments. Measurement systems that use skin surface markers to infer skeletal motion have provided important insight into normal and pathological kinematics, however, accurate arthrokinematics cannot be attained using these systems, especially during dynamic activities. In the past two decades, biplanar videoradiography (BVR) systems have enabled many researchers to directly study the skeletal kinematics of the joints during activities of daily living. To implement BVR systems for the distal upper extremity, videoradiographs of the distal radius and the hand are acquired from two calibrated X-ray sources while a subject performs a designated task. Three-dimensional (3D) rigid-body positions are computed from the videoradiographs via a best-fit registrations of 3D model projections onto to each BVR view. The 3D models are density-based image volumes of the specific bone derived from independently acquired computed-tomography data. Utilizing graphics processor units and high-performance computing systems, this model-based tracking approach is shown to be fast and accurate in evaluating the wrist and distal radioulnar joint biomechanics. In this study, we first summarized the previous studies that have established the submillimeter and subdegree agreement of BVR with an in vitro optical motion capture system in evaluating the wrist and distal radioulnar joint kinematics. Furthermore, we used BVR to compute the center of rotation behavior of the wrist joint, to evaluate the articulation pattern of the components of the implant upon one another, and to assess the dynamic change of ulnar variance during pronosupination of the forearm. In the future, carpal bones may be captured in greater detail with the addition of flat panel X-ray detectors, more X-ray sources (i.e., multiplanar videoradiography), or advanced computer vision algorithms.

Total wrist arthroplasty (TWA) designs suffer from relatively high complication rates when compared to other arthroplasties. Understanding the contact pattern of hip and knee replacement has improved their design and function; however, the in vivo contact pattern of TWA has not yet been examined and is thus the aim of this study. We hypothesized that the center of contact (CoC) is located at the geometric centers of the carpal component and radial component in the neutral posture and that the CoC moves along the principal arcs of curvature throughout primary anatomical motions. Wrist motion and implant kinematics of six patients with the Freedom® total wrist implant were studied during various tasks using biplanar videoradiography. The location of the CoC of the components was investigated by calculating distance fields between the articular surfaces. We found the CoC at the neutral posture was not at the geometric centers but was located 3.5 mm radially on the carpal component and 1.2 mm ulnarly on the radial component. From extension to flexion, the CoC moved 10.8 mm from dorsal to volar side on the carpal component (p < 0.0001) and 7.2 mm from volar to dorsal on the radial component (p = 0.0009). From radial to ulnar deviation, the CoC moved 12.4 mm from radial to ulnar on the carpal component (p < 0.0001), and 5.6 mm from ulnar to radial on the radial component (p = 0.009). The findings of this study may eventually improve TWA success by advancing future designs through a more accurate understating of their kinematic performance in vivo.