Impact of Deep Learning Denoising Algorithm on Diffusion Tensor Imaging of the Growth Plate on Different Spatial Resolutions.

To assess the impact of a deep learning (DL) denoising reconstruction algorithm applied to identical patient scans acquired with two different voxel dimensions, representing distinct spatial resolutions, this IRB-approved prospective study was conducted at a tertiary pediatric center in compliance with the Health Insurance Portability and Accountability Act. A General Electric Signa Premier unit (GE Medical Systems, Milwaukee, WI) was employed to acquire two DTI (diffusion tensor imaging) sequences of the left knee on each child at 3T: an in-plane 2.0 × 2.0 mm2 with section thickness of 3.0 mm and a 2 mm3 isovolumetric voxel; neither had an intersection gap. For image acquisition, a multi-band DTI with a fat-suppressed single-shot spin-echo echo-planar sequence (20 non-collinear directions; b-values of 0 and 600 s/mm2) was utilized. The MR vendor-provided a commercially available DL model which was applied with 75% noise reduction settings to the same subject DTI sequences at different spatial resolutions. We compared DTI tract metrics from both DL-reconstructed scans and non-denoised scans for the femur and tibia at each spatial resolution. Differences were evaluated using Wilcoxon-signed ranked test and Bland-Altman plots. When comparing DL versus non-denoised diffusion metrics in femur and tibia using the 2 mm × 2 mm × 3 mm voxel dimension, there were no significant differences between tract count (p = 0.1, p = 0.14) tract volume (p = 0.1, p = 0.29) or tibial tract length (p = 0.16); femur tract length exhibited a significant difference (p < 0.01). All diffusion metrics (tract count, volume, length, and fractional anisotropy (FA)) derived from the DL-reconstructed scans, were significantly different from the non-denoised scan DTI metrics in both the femur and tibial physes using the 2 mm3 voxel size (p < 0.001). DL reconstruction resulted in a significant decrease in femorotibial FA for both voxel dimensions (p < 0.01). Leveraging denoising algorithms could address the drawbacks of lower signal-to-noise ratios (SNRs) associated with smaller voxel volumes and capitalize on their better spatial resolutions, allowing for more accurate quantification of diffusion metrics.

Polystyrene microplastic-induced endoplasmic reticulum stress contributes to growth plate endochondral ossification disorder in young rat.

BACKGROUND: Previous studies on the effects of microplastics (MPs) on bone in early development are limited. This study aimed to investigate the adverse effects of MPs on bone in young rats and the potential mechanism. METHODS: Three-week-old female rats were orally administered MPs for 28 days, and endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) and ER stress agonist tunicamycin (TM) were added to evaluate the effect of ER stress on toxicity of MPs. The indicators of growth and plasma markers of bone turnover were evaluated. Tibias were analyzed using micro-computed tomography (micro-CT). Histomorphological staining of growth plates was performed, and related gene expression of growth plate chondrocytes was tested. RESULTS: After exposure of MPs, the rats had decreased growth, shortened tibial length, and altered blood calcium and phosphorus metabolism. Trabecular bone was sparse according to micro-CT inspection. In the growth plate, the thickness of proliferative zone substantial reduced while the thickness of hypertrophic zone increased significantly, and the chondrocytes were scarce and irregularly arranged according to tibial histological staining. The transcription of the ER stress-related genes BIP, PERK, ATF4, and CHOP dramatically increased, and the transcription factors involved in chondrocyte proliferation, differentiation, apoptosis, and matrix secretion were aberrant according to RT-qPCR and western blotting. Moreover, the addition of TM showed higher percentage of chondrocyte death. Administration of SAL alleviated all of the MPs-induced symptoms. CONCLUSION: These results indicated that MPs could induce growth retardation and longitudinal bone damage in early development. The toxicity of MPs may attribute to induced ER stress and impaired essential processes of the endochondral ossification after MPs exposure.

Limb Length Discrepancy After Intraosseous Line Malpositioning: A Case Report.

CASE: We will present the case of a 6-year-old girl who presented with a 3-cm limb length discrepancy after intraosseous line placement at age 14 months without other known history of trauma or infection to account for the growth arrest. Imaging revealed a left proximal tibial physeal bar amenable to surgical resection with autologous lipotransfer. At 10 months postoperatively, physical examination and imaging demonstrated a stable 3-cm leg length discrepancy with an interval increase in the length of the left tibia in proportion to the growth of the right side with an increase in valgus alignment that will continue to be monitored and addressed as indicated. CONCLUSION: Pediatric intraosseous line placement presents unique challenges and can ultimately lead to physeal injury and growth arrest in the case of malpositioning.

Stimulation of skeletal stem cells in the growth plate promotes linear bone growth.

Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.

Regulatory Pathways in Growth Plate Chondrocytes that Are Impacted by Matrix Vesicle microRNA Identified by Targeted RISC Pulldown and Sequencing of the Resulting Transcriptome.

During endochondral bone formation, growth plate chondrocytes are differentially regulated by various factors and hormones. As the cellular phenotype changes, the composition of the extracellular matrix is altered, including the production and composition of matrix vesicles (MV) and their cargo of microRNA. The regulatory functions of these MV microRNA in the growth plate are still largely unknown. To address this question, we undertook a targeted bioinformatics approach. A subset of five MV microRNA was selected for analysis based on their specific enrichment in these extracellular vesicles compared to the parent cells (miR-1-3p, miR-22-3p, miR-30c-5p, miR-122-5p, and miR-133a-3p). Synthetic biotinylated versions of the microRNA were produced using locked nucleic acid (LNA) and were transfected into rat growth plate chondrocytes. The resulting LNA to mRNA complexes were pulled down and sequenced, and the transcriptomic data were used to run pathway analysis pipelines. Bone and musculoskeletal pathways were discovered to be regulated by the specific microRNA, notably those associated with transforming growth factor beta (TGFß) and Wnt pathways, cell differentiation and proliferation, and regulation of vesicles and calcium transport. These results can help with understanding the maturation of the growth plate and the regulatory role of microRNA in MV.

Chondrocyte hypertrophy in the growth plate promotes stress anisotropy affecting long bone development through chondrocyte column formation.

The length of long bones is determined by column formation of proliferative chondrocytes and subsequent chondrocyte hypertrophy in the growth plate during bone development. Despite the importance of mechanical loading in long bone development, the mechanical conditions of the cells within the growth plate, such as the stress field, remain unclear owing to the difficulty in investigating spatiotemporal changes within dynamically growing tissues. In this study, the mechanisms of longitudinal bone growth were investigated from a mechanical perspective through column formation of proliferative chondrocytes within the growth plate before secondary ossification center formation using continuum-based particle models (CbPMs). A one-factor model, which simply describes essential aspects of a biological signaling cascade regulating cell activities within the growth plate, was developed and incorporated into CbPM. Subsequently, the developmental process and maintenance of the growth plate structure and resulting bone morphogenesis were simulated. Thus, stress anisotropy in the proliferative zone that affects bone elongation through chondrocyte column formation was identified and found to be promoted by chondrocyte hypertrophy. These results provide further insights into the mechanical regulation of multicellular dynamics during bone development.

A missed opportunity: A scoping review of the effect of sex and age on osteoarthritis using large animal models.

OBJECTIVE: The objective was to critically analyze the published literature accounting for sex differences and skeletal age (open vs. closed physis) in preclinical animal models of OA, including the disaggregation of data by sex and skeletal maturity when data is generated from combined sex and/or multi-aged cohorts without proper confounding. METHOD: A scoping literature review of PubMed, Web of Science, EMBASE, and SCOPUS was performed for studies evaluating the effect of sex and age in experimental studies and clinical trials utilizing preclinical large animal models of OA. RESULTS: A total of 9727 papers were identified in large animal (dog, pig, sheep, goat, horse) models for preclinical OA research, of which 238 ex vivo and/or in vivo studies disclosed model type, animal species, sex, and skeletal age sufficient to analyze their effect on outcomes. Dogs, followed by pigs, sheep, and horses, were the most commonly used models. A paucity of preclinical studies evaluated the effect of sex and age in large animal models of naturally occurring or experimentally induced OA: 26 total studies reported some kind of analysis of the effects of sex or age, with 4 studies discussing the effects of sex only, 11 studies discussing the effects of age only, and 11 studies analyzing both the effects of age and sex. CONCLUSION: Fundamental to translational research, OARSI is uniquely positioned to develop recommendations for conducting preclinical studies using large animal models of OA that consider biological mechanisms linked to sex chromosomes, skeletal age, castration, and gonadal hormones affecting OA pathophysiology and treatment response.

Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice.

BACKGROUND: 3 M syndrome is first reported in 1975，which characterized by severe pre- and postnatal growth retardation, skeletal malformation and facial dysmorphism. These three genes (CUL7, OBSL1 and CCDC8) have been identified to be respond for 3 M syndrome, of which CUL7 is accounting for approximately 70%. To date, the molecular mechanism underlying the pathogenesis of 3 M syndrome remains poorly understood. Previous studies showed that no Cul7-/- mice could survive after birth, because of growth retardation at late gestational stage and respiratory distress after birth. The establishment of the animal model of cartilage specific Cul7 knockout mice (Cul7fl/fl;Col2a1-CreERT2 mice) has confirmed that Cul7fl/fl;Col2a1-CreERT2 mice can be selective in a time- and tissue-dependent manner, which can provide an experimental basis for further research on severe genetic diseases related to growth plates. OBJECTIVE: To establish a model of Cul7fl/fl;Col2a1-CreERT2 mice based on Cre/LoxP system, and to further observe its phenotype and morphological changes in growth plate. METHODS: The Cul7fl/fl;Col2a1-CreERT2 mice were taken as the experimental group, while the genotype of Cul7fl/+;Col2a1-CreERT2 mice were used as the control group. The gross morphological features and X-ray films of limbs in the two groups were observed every week for 3-6 consecutive weeks, and the length of the mice from nose to the tail, the length of femur and tibia were recorded. In the meantime, The histological morphology of tibial growth plates was compared between the two groups. RESULTS: A preliminary model of Cul7fl/fl;Col2a1-CreERT2 mice was established. The Cul7fl/fl;Col2a1-CreERT2 mice had abnormally short and deformed limbs (P<0.05), increased thickness of growth plate, the disorderly arranged chondrocyte columns, decreased number of cells in the proliferation zone, changes in the shape from flat to round, obviously expanded extracellular matrix, and disordered arrangement, thickening and loosening of bone trabecula at the proximal metaphysis of the femur. CONCLUSIONS: The knockout of Cul7 gene may affect both the proliferation of chondrocytes and the endochondral osteogenesis, confirming that Cul7 is essential for the normal development of bone in the body.

N-cadherin and ß1 integrin coordinately regulate growth plate cartilage architecture.

Spatial and temporal regulation of chondrocyte maturation in the growth plate drives growth of many bones. One essential event to generate the ordered cell array characterizing growth plate cartilage is the formation of chondrocyte columns in the proliferative zone via 90-degree rotation of daughter cells to align with the long axis of the bone. Previous studies have suggested crucial roles for cadherins and integrin ß1 in column formation. The purpose of this study was to determine the relative contributions of cadherin- and integrin-mediated cell adhesion in column formation. Here we present new mechanistic insights generated by application of live time-lapse confocal microscopy of cranial base explant cultures, robust genetic mouse models, and new quantitative methods to analyze cell behavior. We show that conditional deletion of either the cell-cell adhesion molecule Cdh2 or the cell-matrix adhesion molecule Itgb1 disrupts column formation. Compound mutants were used to determine a potential reciprocal regulatory interaction between the two adhesion surfaces and identified that defective chondrocyte rotation in a N-cadherin mutant was restored by a heterozygous loss of integrin ß1. Our results support a model for which integrin ß1, and not N-cadherin, drives chondrocyte rotation and for which N-cadherin is a potential negative regulator of integrin ß1 function.

Rheb1 is required for limb growth through regulating chondrogenesis in growth plate.

Ras homology enriched in the brain (Rheb) is well established as a critical regulator of cell proliferation and differentiation in response to growth factors and nutrients. However, the role of Rheb1 in limb development remains unknown. Here, we found that Rheb1 was dynamically expressed during the proliferation and differentiation of chondrocytes in the growth plate. Given that Prrx1+ limb-bud-like mesenchymal cells are the source of limb chondrocytes and are essential for endochondral ossification, we conditionally deleted Rheb1 using Prrx1-Cre and found a limb dwarfism in Prrx1-Cre; Rheb1fl/fl mice. Normalized to growth plate height, the conditional knockout (cKO) mice exhibited a significant decrease in column count of proliferative zones which was increased in hypertrophic zones resulting in decreased growth plate size, indicating abnormal endochondral ossification. Interestingly, although Rheb1 deletion profoundly inhibited the transcription factor Sox9 in limb cartilage; levels of runx2 and collagen type 2 were both increased. These novel findings highlight the essential role of Rheb1 in limb growth and indicate a complex regulation of Rheb1 in chondrocyte proliferation and differentiation.

Physeal Fractures of the Distal Ulna: Incidence and Risk Factors for Premature Growth Arrest.

BACKGROUND: The aim of this study is to assess the rate of distal ulnar growth arrest following physeal fracture and to identify specific risk factors for premature physeal closure. METHODS: A retrospective review of patients with a distal ulnar physeal fracture was performed at a single United States children's hospital. Patients without 6-month follow-up were excluded. Patient demographics, injury characteristics, treatment, and outcomes were abstracted. Fractures were classified by the Salter-Harris (SH) system. All follow-up radiographs were reviewed for changes in ulnar variance or signs of premature physeal arrest. RESULTS: Fifty-six children with distal ulnar physeal fracture at a mean age of 10.7±3.3 years were included with a mean follow-up of 1.9 years. The most common fracture pattern was a SH II (52.7%), versus SH I (29.1%), SH III (9.1%), and SH IV (9.1%). Of displaced fractures (41.1%), the mean translation was 40.2±38.3% the and mean angulation was 24.8±20.9 degrees. Eleven fractures (19.6%) demonstrated radiographic signs of growth disturbance, including 3 patients (5.4%) with growth disturbance but continued longitudinal growth and 8 patients (14.3%) with complete growth arrest. The average ulnar variance was -3.4 mm. Three patients underwent subsequent surgical reconstruction including ulnar lengthening with an external fixator, distal ulna completion epiphysiodesis with distal radius epiphysiodesis, and ulnar corrective osteotomy. Patients with displaced fractures and SH III/IV fractures were more likely to develop a growth disturbance (34.8% vs. 3.2%, P =0.003; 50.0% vs. 11.1%, P =0.012, respectively). Children with less than 2 years of skeletal growth remaining at the time of injury had a higher risk of growth disturbance (46.2% vs. 9.5%, P =0.007). CONCLUSIONS: SH III and IV fractures are more common injury patterns in the distal ulna compared with the distal radius. Growth disturbance or growth arrest occurs in ~20% of distal ulnar physeal fractures. Displaced fractures, intra-articular fractures, fractures requiring open reduction, and older children are at increased risk of distal ulnar growth arrest and should be followed more closely. LEVEL OF EVIDENCE: Level IV--case series.

Physeal Closure and Fracture Pattern in Adolescent Transitional Distal Radius Fractures.

PURPOSE: To show a correlation between grade of physeal closure and fracture pattern in adolescent transitional distal radius fractures. METHODS: A retrospective chart review was performed of 490 distal radius fractures, ages 14 to 18, at a single institution between 2007 and 2020. A board-certified orthopaedic hand surgeon reviewed all images. Thirty-six distal-radius fractures were considered adolescent transitional fractures. The review included Salter-Harris classification, fracture fragments, and grade of physeal closure. RESULTS: Distal radial physeal closure is 50 times more likely to be of a higher grade in the presence of Salter-Harris type IV fractures ( P <0.001). Closure of the physis is also 7.37 and 13.08 times more likely to be of higher grade in the absence of a dorsal metaphyseal fracture and in the presence of an ulnar corner fracture, respectively ( P =0.011 and 0.021). CONCLUSION: Adolescent transitional fractures of the distal radius occur when the growth plate has a partial closure. The closure pattern of the distal radial physis begins centrally, with subsequent ulnar and then radial closure. In this cohort, there is a correlation between grade of physeal closure and fracture pattern in adolescent transitional distal radius fractures. LEVEL OF EVIDENCE: Level IV-diagnostic.

Percutaneous transphyseal screw induces varus proximal femoral growth modulation in a growing pig model-A three-dimensional analysis.

Bone and joint angular deformities are common pediatric orthopedic problems that are often corrected surgically. Previous studies successfully demonstrated proximal femoral growth modulation in animal models, however outcome measurements were limited by two-dimensional analysis. In this study, six Yorkshire cross male piglets were treated with unilateral percutaneous transphyseal screw placement across the medial aspect of the proximal femoral physis and analyzed using three-dimensional (3D) techniques. Three primary outcome measures were considered-physis angle, version, and femoral length. Compared to paired controls, all treated femurs displayed varus correction and shortening after an average treatment period of 10 weeks. The amount of varus change was 11.6 ± 2.8° (mean ± SD) (p = 0.0002, 95% confidence interval [CI] [8.659, 14.589]) and shortening was 4.3 ± 1.6 mm (p = 0.0011, 95% CI [2.672, 5.942]). Four animals demonstrated retroversion and two demonstrated anteversion compared to controls (4.1 ± 5.4° retroversion, p = 0.1169, 95% CI [-1.483, 9.765]). The amount of varus correction was strongly correlated with the orientation of the screw relative to the medial/lateral axis of the physis (r = -0.887, p = 0.0183, 95% CI [-0.988, -0.271]). The amount and direction of version was strongly correlated with how eccentrically anterior or posterior the screw was placed relative to the center of the physis (r = -0.850, p = 0.0322, 95% CI [-0.983, -0.123]) as well as the angle of the screw relative to the posterior condylar axis of the femur (r = -0.980, p = 0.0006, 95% CI [-0.998, -0.822]). This study is the first to use 3D analysis to quantify proximal femur growth modulation and identify associations between the growth modulation outcomes and screw placement parameters.

Physeal Bar Formation After Pediatric Medial Malleolus Fractures.

Pediatric medial malleolus fractures are commonly Salter-Harris (SH) type III or IV fractures of the distal tibia and are associated with a risk of physeal bar formation and subsequent growth disturbance. The purpose of this study was to determine the incidence of physeal bar formation following pediatric medial malleolus fracture and evaluate for patient and fracture characteristics predictive of physeal bar formation. Seventy-eight consecutive pediatric patients during a 6-year period who had either an isolated medial malleolar or a bimalleolar ankle fracture were retrospectively reviewed. Forty-one of 78 patients had greater than 3 months of radiographic follow-up and comprised the study population. Medical records were reviewed for demographic information, mechanism of injury, treatment, and need for further surgery. Radiographs were reviewed to assess for initial fracture displacement, adequacy of fracture reduction, SH type, percentage of the physeal disruption from the fracture, and physeal bar formation. Twenty-two of 41 patients (53.7%) developed a physeal bar. The mean time to diagnosis of physeal bar was 4.9 months (range, 1.6-11.8 months). Twenty-seven percent (6 of 22) of bars were diagnosed at greater than 6 months from injury. Adequacy of reduction was predictive of physeal bar formation, although all patients were reduced to within 2 mm. The mean residual displacement of patients with a bar was 1.2 mm compared with 0.8 mm for those without a bar (P=.03). Because the bar formation rate is greater than 50% on radiographs, routine radiographic assessment of all pediatric medial malleolar fractures should continue for at least 12 months after injury. [Orthopedics. 2024;47(1):e33-e37.].

Muscle forces acting on the greater trochanter lead to a dorsal warping of the apophyseal growth plate.

The apophyseal growth plate of the greater trochanter, unlike most other growth plates of the human body, exhibits a curved morphology that results in a divergent pattern resembling an open crocodile mouth on plain antero-posterior radiographs. To quantify the angular alignment of the growth plate and to draw conclusions about the function of the muscles surrounding it, we analyzed 57 MRI images of 51 children and adolescents aged 3-17 years and of six adults aged 18-52 years. We measured the angulation of the plate relative to the horizontal plane (AY angle) and the trajectories of the muscles attaching to the greater trochanter of the proximal femur. From anterior to posterior, the AY angle shows a decrease of 33.44°. In the anterior third, the cartilage is angled at a mean of 51.64°, and in the posterior third, the mean angulation is 18.6°. This indicates that the cartilage in the anterior region of the greater trochanteric apophysis is subject to more vertically oriented force vectors compared to the posterior region, as the growth plates align perpendicular to the force vectors acting on them. Combining the measured muscle trajectories with the physiological cross-sectional areas (PCSA) available from the literature revealed that, in addition to the known internal and external lateral traction ligament systems, a third, dorsally located traction ligament system exists that may be responsible for the dorsal deformation of the AY angle.

Use of a Modified Intramedullary Pinning Technique for Distal Femoral Physeal Salter-Harris Type I and II Fracture Management: A Retrospective Study of 31 Cats.

OBJECTIVE: To report a modified intramedullary pinning technique, and associated outcomes, for distal femoral physeal Salter-Harris type I and II fracture management in cats. STUDY DESIGN: Retrospective study including client-owned cats presented between November 2014 and February 2022 with distal femoral physeal fractures treated with an intramedullary pin and one antirotational pin inserted in the lateral femoral condyle. Collected data included signalment, fracture characteristics according to the Salter-Harris classification, surgical data (intramedullary and antirotational pin sizes), and outcome data (radiographic and functional outcomes and complications). RESULTS: Thirty-one cats were included in this study. Bone healing was radiographically confirmed 6 to 8 weeks postoperatively in all cases. The majority of cats (30/31) were classified as full functional outcomes at mid-term follow-up. The overall mid-term complication rate was 3% (1/31). Implant migration was not observed and implant removal was not needed in any case. CONCLUSION: The modified intramedullary pinning technique for distal femoral Salter-Harris I and II fracture management in cats was associated with an full functional outcome.

Physeal Migration During Knee-guided Growth With Tension Band Plates: Influence of Implant Position.

OBJECTIVE: Physeal migration during guided growth with tension band plates (TBPs) has been poorly described. The positioning factors associated with this phenomenon and its clinical implications are unknown. Our aim is to determine the influence of implant position on the risk of physeal migration during knee-guided growth with TBP. METHODS: Retrospective study of 491 patients who underwent temporary hemi or epiphysiodesis with TBP around the knee between 2007 and 2019. We identified 29 patients who presented physeal migration during follow-up. Demographic and clinical data were collected, and the following measures were obtained from the immediate postoperative radiographs: epiphyseal screw base-physis distance/epiphyseal screw tip-physis distance, interscrew angle, epiphyseal screw-physis angle(ES-PHa)/metaphyseal screw-physis angle, plate-physis angle, epiphyseal screw-plate angle/metaphyseal screw-plate angle, and epiphyseal screw-physis length ratio. Using follow-up radiographs, the type of physeal migration of the epiphyseal screw (touch, occupy, or traverse) and the status of the physis after implant removal (unaltered, physeal bar, and skeletal maturity) were also recorded. A descriptive analysis of the cases and a case-control comparison of imaging studies were performed. RESULTS: The median patient age at intervention was 12.2 years (interquartile range: 11.3 to 14.1), and 76% were males. A statistically significant difference between cases and controls was obtained for epiphyseal screw base-physis distance (3.7 vs 6.3; P = 0.029), epiphyseal screw tip-physis distance (3.6 vs 7.85; P = 0.002), ES-PHa (-0.1 vs 7.45; P = 0.007), and plate-physis angle (85.45 vs 88.60; P = 0.012). In a categorical analysis, a significant difference was found for the ES-PHa categories ( P = 0.002) and for the ES-PHa/metaphyseal screw-physis angle categorical pair ( P = 0.018). In 16, 17, and 12 cases the physis was touched, occupied, or traversed, respectively, although we found no physeal alterations after plate removal. CONCLUSIONS: In our study, physeal migration of TBP is not an uncommon phenomenon, although no physeal abnormalities were detected. Convergent placement of the epiphyseal screw with the base or tip close to the physis should be avoided as this position is associated with a higher risk of physeal migration. LEVEL OF EVIDENCE: Level III-case-control study.

Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency.

The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-Indian hedgehog feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+ resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we specifically activated Hedgehog signaling in PTHrP+ resting chondrocytes and traced the fate of their descendants using a tamoxifen-inducible Pthrp-creER line with patched-1-floxed and tdTomato reporter alleles. Hedgehog-activated PTHrP+ chondrocytes formed large, concentric, clonally expanded cell populations within the resting zone ("patched roses") and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP+ cell descendants migrated away from the growth plate and transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a potentially novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+ skeletal stem cells.

Epiphyseal cartilage vascular architecture at the distal humeral osteochondritis dissecans predilection site in juvenile pigs.

Failure of endochondral ossification due to interruption of the vascular supply to the epiphyseal cartilage is a critical step in the development of osteochondritis dissecans (OCD). Herein we describe the vascular architecture of the distal humeral epiphyseal cartilage in pigs and identify characteristic features that have been associated with sites predisposed to OCD development across species. Distal humeral specimens were harvested from pigs (n = 5, ages = 1, 10, 18, 30, and, 42 days old) and imaged at 9.4T magnetic resonance imaging (MRI) using a 3D gradient recalled echo sequence. The MRI data were processed using a quantitative susceptibility mapping (QSM) pipeline to visualize the vascular architecture. Specimens were also evaluated histologically to identify the presence of ischemic epiphyseal cartilage necrosis (osteochondrosis [OC]-latens) and associated failure of endochondral ossification (OC-manifesta). The QSM data enabled visualization of two distinct vascular beds arising from the perichondrium at the lateral and medial aspects of the distal humeral epiphysis. Elongated vessels originating from these beds coursed axially to supply the lateral and medial thirds of epiphyseal cartilage. At 18 days of age and older, a shift from perichondrial to transosseous blood supply was noted axially, which appeared more pronounced on the lateral side. This shift coincided with histologic identification of OC-latens (30- and 42-day-old specimens) and OC-manifesta (18- and 42-day-old specimens) lesions in the corresponding regions. The vascular anatomy and its evolution at the distal humeral epiphysis closely resembles that previously reported at predilection sites of knee OCD, suggesting a shared pathophysiology between the knee and elbow joints.