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Bone & Joint Research
Vol. 11, Issue 3 | Pages 162 - 170
14 Mar 2022
Samvelyan HJ Huesa C Cui L Farquharson C Staines KA

Aims. Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 (Socs2. -/-. ) display accelerated bone growth. Methods. We examined vulnerability of Socs2. -/-. mice to OA following surgical induction of disease (destabilization of the medial meniscus (DMM)), and with ageing, by histology and micro-CT. Results. We observed a significant increase in mean number (wild-type (WT) DMM: 532 (SD 56); WT sham: 495 (SD 45); knockout (KO) DMM: 169 (SD 49); KO sham: 187 (SD 56); p < 0.001) and density (WT DMM: 2.2 (SD 0.9); WT sham: 1.2 (SD 0.5); KO DMM: 13.0 (SD 0.5); KO sham: 14.4 (SD 0.7)) of growth plate bridges in Socs2. -/-. in comparison with WT. Histological examination of WT and Socs2. -/-. knees revealed articular cartilage damage with DMM in comparison to sham. Articular cartilage lesion severity scores (mean and maximum) were similar in WT and Socs2. -/-. mice with either DMM, or with ageing. Micro-CT analysis revealed significant decreases in SCB thickness, epiphyseal trabecular number, and thickness in the medial compartment of Socs2. -/-. , in comparison with WT (p < 0.001). DMM had no effect on the SCB thickness in comparison with sham in either genotype. Conclusion. Together, these data suggest that enhanced GH signalling through SOCS2 deletion accelerates growth plate fusion, however this has no effect on OA vulnerability in this model. Cite this article: Bone Joint Res 2022;11(3):162–170


Bone & Joint Research
Vol. 3, Issue 11 | Pages 310 - 316
1 Nov 2014
Tomaszewski R Bohosiewicz J Gap A Bursig H Wysocka A

Objectives. The aim of this experimental study on New Zealand’s white rabbits was to investigate the transplantation of autogenous growth plate cells in order to treat the injured growth plate. They were assessed in terms of measurements of radiological tibial varus and histological characteristics. . Methods. An experimental model of plate growth medial partial resection of the tibia in 14 New Zealand white rabbits was created. During this surgical procedure the plate growth cells were collected and cultured. While the second surgery was being performed, the autologous cultured growth plate cells were grafted at the right tibia, whereas the left tibia was used as a control group. . Results. Histological examinations showed that the grafted right tibia presented the regular shape of the plate growth with hypertrophic maturation, chondrocyte columniation and endochondral calcification. Radiological study shows that the mean tibial deformity at the left angle was 20.29° (6.25 to 33) and 7.21° (5 to 10) in the right angle. . Conclusion. This study has demonstrated that grafting of autogenous cultured growth plate cells into a defect of the medial aspect of the proximal tibial physis can prevent bone bridge formation, growth arrest and the development of varus deformity. Cite this article: Bone Joint Res 2014;3:310–16


Bone & Joint Research
Vol. 3, Issue 9 | Pages 273 - 279
1 Sep 2014
Vasiliadis ES Kaspiris A Grivas TB Khaldi L Lamprou M Pneumaticos SG Nikolopoulos K Korres DS Papadimitriou E

Objectives. The aim of this study was to examine whether asymmetric loading influences macrophage elastase (MMP12) expression in different parts of a rat tail intervertebral disc and growth plate and if MMP12 expression is correlated with the severity of the deformity. Methods. A wedge deformity between the ninth and tenth tail vertebrae was produced with an Ilizarov-type mini external fixator in 45 female Wistar rats, matched for their age and weight. Three groups were created according to the degree of deformity (10°, 30° and 50°). A total of 30 discs and vertebrae were evaluated immunohistochemically for immunolocalisation of MMP12 expression, and 15 discs were analysed by western blot and zymography in order to detect pro- and active MMP12. Results. No MMP12 expression was detected in the nucleus pulposus. Expression of MMP12 in the annulus progressively increased from group I to groups II and III, mainly at the concave side. Many growth plate chondrocytes expressed MMP12 in the control group, less in group I and rare in groups II and III. Changes in cell phenotype and reduction of cell number were observed, together with disorganisation of matrix microstructure similar to disc degeneration. ProMMP12 was detected at the area of 54 kDa and active MMP12 at 22 kDa. Conclusions. Expression of MMP12 after application of asymmetric loading in a rat tail increased in the intervertebral disc but decreased in the growth plate and correlated with the degree of the deformity and the side of the wedged disc. Cite this article: Bone Joint Res 2014;3:273–9


Orthopaedic Proceedings
Vol. 85-B, Issue SUPP_I | Pages 1 - 1
1 Jan 2003
Roach H Shukunami C Hiraki Y
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Chondromodulin-I (ChM-I) is a bifunctional autocrine regulator of cartilage, initially isolated from fetal bovine epiphyseal cartilage. 1. ChM-I stimulates matrix synthesis of chondrocytes, but inhibits the growth of endothelial cells. 1,. 2. thus ChM-I may be one of the anti-angiogenic molecules present in cartilage. In fetal bovine bone, ChM-I was expressed by all epiphyseal and growth plate chondrocytes except hypertrophic chondrocytes and was present in the matrix throughout the epiphysis and the growth plate, except the hypertrophic zone . 2,. 3. , consistent with its proposed role as anti-angiogenic factor. To examine the possible role of chondromodulin-I in relation to angiogenesis at the vascular front, we studied the immunolocalisation in femoral growth plates from young and mature rats (2–16 weeks) as well as aged rats (62–80 weeks), using a rabbit polyclonal antibody raised against the entire region of mature human recombinant ChM-I. In 2-week old rats, ChM-I was synthesised by all epiphyseal chondrocytes and strong immunostaining was found in the matrix. In the growth plates, ChM-I staining was present in chondrocytes and matrix of the reserve, proliferating and maturing zones with loss of staining in the hypertrophic zone. However, ChM-I was also present where cartilage canals had penetrated into the chondroepiphysis. In 4–16 week old rats, there was a progressive change in the localisation of ChM-I. Hypertrophic chondrocytes also became positive for ChM-I, while cellular staining gradually disappeared from the other zones. By 12–16 weeks, very strong immunostaining was present almost exclusively on the inner perimeter of the lacunae of hypertrophic chondrocytes. As lacunae were opened at the vascular front, ChM-I initially remained on the cartilage-side of the lacunae, and then disappeared completely. In aged rats, very little ChM-I was present in the cells and matrix of the growth plates, except where remodelling had occurred or chondrocytes had become re-activated. The rate of longitudinal growth in rats is high between 1–5 weeks, then declines until skeletal maturity at approximately 12 weeks, after which a very slow rate of growth continues until 26 weeks. In young rats, the loss of ChM-I in the hypertrophic zone was as expected for an anti-angiogenic factor, i.e. loss was required before vascular invasion could take place. However, the same did not apply to cartilage canal formation, since there was no loss of ChM-I around cartilage canals. The change in the localisation of ChM-I in mature rats, in particular the very intense immunolocalisation around hypertrophic chondrocytes, might be related to the reduced rate of growth. It is possible that rapid vascular invasion must be slowed down in these growth plates and that ChM-I prevented vascular invasion until degraded by proteases, such as MMP-9. The relative absence of ChM-I in the stationary growth plates of aged rats suggests that other anti-angiogenic factors prevent vascular invasion in these growth plates


Orthopaedic Proceedings
Vol. 84-B, Issue SUPP_II | Pages 150 - 150
1 Jul 2002
Mehta G Oreffo RO Langley-Evans SC Cooper C Clarke NMP Roach HI
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Cohort studies in humans have suggested that the peak bone mass attained at skeletal maturity may be programmed in utero. To investigate which aspects of bone development might be influenced in utero, we utilised a rat model of maternal protein insufficiency, which has previously been used to demonstrate the fetal origin of adult hypertension. In rodents, a growth plate remains present throughout life, even after longitudinal growth ceases. Generally, the height of the growth plate is related to the rate of bone growth. Fast growing bones have maximal height growth plates, and as bone growth slows down the height decreases until it remains stationary. The aim of this study was to compare the morphology of long bones in aged rats that had been subjected to protein insufficiency in utero with that of controls. Rat dams were fed either an 18% casein control diet or a 9% casein low protein diet from conception until the end of pregnancy. The offspring were fed a normal diet until death (~72 weeks), when bone density was measured by dual energy X-ray absorptiometry (DEXA) and the tibiae and femurs were processed for histology. The offspring of rats from the low protein group had a significantly lower bone mass, as assessed by DEXA. The major differences in bone structure were found in the growth plates, which were very irregular without the usual zones of resting, proliferating and hypertrophic chondrocytes. A number of unusual cellular events were noted to have taken place subsequent to cessation of growth, including: a) elimination of all chondrocytes in a number of regions, resulting in vast acellular areas; b) formation of chondroid bone and/or transdifferentiation of chondrocytes to bone-forming cells in other regions; c) partial resorption of those latter regions while the acellular regions were not resorbed; d) ‘horizontal’ apposition of bone against a smooth metaphyseal edge of the growth plate. To compare the growth plates from the low and high protein groups semi-quantitatively, the degrees of the above features were scored. In addition, the heights of the growth plates were were assessed by two independent measurements. In the low protein group, the height of the growth plate were found to be significantly greater (p< 0.001). Additionally, the growth plates from this group of animals were observed to be more irregular with regards to all the features outlined above. These findings are consistent with the hypothesis that growth trajectory and bone mass are programmed in early life. The increased height of the growth plate in animals undernourished in utero may reflect the cessation of growth at an earlier age. The increased irregularity of the growth plate in this group of animals may infer an earlier onset of age-related changes within the growth cartilage


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_3 | Pages 21 - 21
1 Apr 2018
Caron M Castermans T van Rietbergen B Haartmans M van Rhijn L Witlox A Welting T
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INTRODUCTION. Endochondral ossification in the growth plate is directly responsible for skeletal growth and its de novo bone-generating activity. Growth plates are vulnerable to disturbances that may lead to abnormal skeletal development. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used analgesics but have been reported to impair endochondral ossification-driven fracture healing. Despite the general awareness that NSAIDs affect endochondral ossification, the consequences of NSAIDs on skeletal development are unknown. We hypothesise that the NSAID celecoxib leads to impaired growth plate development and consequently impairs skeletal development. METHODS. Healthy skeletally immature (5 weeks old) C57BL/6 mice were treated for ten weeks with celecoxib (daily oral administration 10 mg/kg) or placebo (water) (institutional approval 2013–094) (n=12 per group). At 15 weeks postnatally, total growth plate thickness, the thickness of specific growth plate zones, (immuno)histological analysis of extracellular matrix composition in the growth plate, cell number and cell size, longitudinal bone growth and bone micro-architecture by micro-CT were analysed. Inhibition of COX-2 activity was confirmed by determining PGE2 levels in plasma using an ELISA. RESULTS. No significant difference in total growth plate thickness or thickness of the resting zone, proliferative or hypertrophic zone was found between groups. Staining of growth plate extracellular matrix components revealed, however, a significantly higher proteoglycan content and less collagen type II staining in the proliferative zone. In the hypertrophic zone of the growth plates of celecoxib treated mice collagen type X was hardly detectable as compared to placebo mice. In addition, a significantly decreased cell number was observed in the hypertrophic zone of the growth plate and cells were significantly smaller in the celecoxib group. Micro-CT analysis of the subchondral bone region directly beneath the growth plate showed significantly higher bone density, bone volume density and trabecular thickness following celecoxib treatment. Despite the detected differences in extracellular matrix composition of the growth plate, no difference was found in the length of the tibia in celecoxib treated mice. DISCUSSION. In summary, there are no measurable differences found in murine skeletal formation as a result of treatment with celecoxib in this study. However, there are notable phenotypic features found in the maturation of the growth plate (hypertrophic zone and subchondral bone) as a result from the celecoxib treatment, of which the potential consequences we do not yet understand. SIGNIFICANCE. When follow-up actions from the use of celecoxib on the growing individual are found this may warrant re-evaluation for the use of celecoxib in these individuals


Orthopaedic Proceedings
Vol. 90-B, Issue SUPP_III | Pages 470 - 470
1 Aug 2008
Hobbs H Dunn R Dix-Peek S Wieselthaler N Hoffman E
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Physeal bar resection for partial growth plate arrest was first described by Langenskjold in 1967. The initial enthusiasm by Peterson (1989) who found that 83% of patients resumed physeal growth was tempered by Birch (1992) who only had 33% success. Poor results were due to failure to resume growth or premature growth arrest. We retrospectively reviewed 21 physeal bar resections performed in 19 children from 1987 to 2003. The average age at surgery was 8.2 years (range 3–12 years). The aetiology of the physeal arrest was : growth plate fracture (8), meningococcal septicaemia (5), osteitis (3; 2 neonatal), dysplasia (3), gunshot (1) and idiopathic (1). The commonest site was the distal femur (12; 5 due to growth plate fracture), followed by the proximal tibia (5; 3 due to meningococcal septicaemia), and the distal tibia (4; 2 due to growth plate fractures). Assessment of the size and location of the bar was with biplanar tomography in 7, MRI in 5 and both in 7. We found equal accuracy with both modalities, but currently prefer MRI. The bar was plotted on an anterior-posterior and lateral map of the growth plate. The average size of the bar was 25% (range 15 to 50%) of the area of the growth plate. Only 3 bars were larger than 30%. Fifteen of the bars were peripheral, 5 linear and 1 central. Results were classified poor if there was no resumption of growth or if premature growth plate arrest occurred, good if there was resumption of growth which continued to maturity or to follow-up, and excellent if the growth exceeded the expected growth. There were 5 (24%) poor results; all failed to resume growth. Three bars exceeded 30% and 2 were due to meningococcal septicaemia. The remaining 16 bars were followed up for a range of 2 to 12 years; 10 to maturity. Four (19%) had an excellent and 12 (57%) had a good result. The authors conclude that physeal bar resection is a worthwhile procedure if the size of the bar is equal to or less than 30% of the area of the growth plate. In growth arrest due to meningococcal septicaemia we only had a 60% success rate


Orthopaedic Proceedings
Vol. 98-B, Issue SUPP_9 | Pages 73 - 73
1 May 2016
Nakamura T Niki Y Nagai K Sassa T Heldreth M
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Introduction. Kinematically or anatomically aligned total knee arthroplasty (TKA) has been reported to provide improved clinical outcomes by replicating patient's original joint line [1][2]. It has been known that tibial (joint line) varus varies among patients, and the tibial varus would increase over progression of arthritis and bone remodeling. For those patients with significant deformity, the current tibial varus may significantly differ from its pre-diseased state. In this exploratory study, geometry and alignment of the tibial growth plate were measured with respect to tibial anatomical landmarks in order to better understand modes of tibial deformity and seek possible application in reconstructing pre-diseased joint alignment. Methods. CT scans of sixteen healthy Japanese knees (M6:F10, Age 31.9±13.9 years) were studied. Three-dimensional reconstruction models were created using Mimics 17 (Materialise, Leuven, Belgium). First, a mid-sagittal tibial reference plane, for comparing the varus/valgus orientation of the tibial plateau to that of the growth plate, was defined by the medial margin of the tibial tuberosity, origin of the PCL and center of the foot joint. The tibial plateau (or joint line plane) was determined from three points; dwell point of femur (aligned in extension) on lateral tibial articular surface, and two points at anterior and posterior rim of medial tibial articular surface sampled in the sagittal view and coinciding with dwell point of femur on medial tibia. Then, a three-dimensional model of the tibial growth plate was extracted using the Livewire function and mask editing tools in Mimics. To determine 3D orientation of the growth plate (GP), the vertical mass moment of inertia axis was calculated for the 3D model. The inertia axes were also determined for medial and lateral half of the GP (Figure 1). Results. Tibial plateau (TP) had 2.39±1.72 degrees of varus in coronal view and 11.12±3.90 degrees of posterior inclination in sagittal view. The shape of the GP is noticeably different between medial and lateral. The medial half tends to incline posteriorly towards medial, while the lateral half is twisted anteriorly. In coronal view, GP axis was in 1.27±1.49 degrees valgus to midsagittal plane. Normal axis of the TP was in varus to the GP axis by 3.66±1.79 degrees. The GP medial half was in 5.81±2.49 degrees valgus and 1.63±2.59 degrees anteriorly inclined with respect to the TP. The GP lateral half was in 11.65±2.07 degrees varus and 18.66±4.44 degrees anteriorly inclined relative to the TP. Discussion. The preliminary results from 16 healthy knees suggested that the tibial growth plate is aligned to midsagittal plane and tibial plateau in varus/valgus orientations with relatively small variations. More study samples will be required to validate usefulness of this method in surgical planning. Distinctive shape difference for medial and lateral half of the growth plate was also observed. Future study should also include diseased knees with various levels of deformities


Orthopaedic Proceedings
Vol. 88-B, Issue SUPP_I | Pages 125 - 126
1 Mar 2006
De Pablos J Fernandez J Gonzalez SG Arrese A Avilla A Corchuelo C
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Purposes:. See if permanent damage of the growth plate after physeal distraction is the rule and. Identify factors with influence on the viability of the physis after physeal distraction. Introduction: Surgeons have always been concerned about the fate of the growth plate after physeal distraction and for that reason this technique has usually been considered only in patients nearing maturity. Previous experimental work has shown that the velocity of distraction has an influence on the viability of the growth plate at follow-up (recommended rate: 0.5 mm/day). Clinically, it has also been our observation that the condition of the physis prior to distraction is another important factor related to physeal function in the long term. Patients and methods: Since 1987 we have used low velocity physeal distraction in 43 bone segments of which 37 cases have been followed-up at least for 24 months and this has been the group included in this study. The indications were lengthening (14), angular deformity correction (19) and resection of benign bone tumours (4). Most patients (24) were older than 10 y.o. and 22 of them were followed-up until maturity. We have retrospectively reviewed these patients looking at the radiological morphology and function of the distracted growth plate at follow-up. Results: Out of the 24 children older than 10 y.o., twenty showed a premature complete physeal closure. We looked with interest at the 13 cases younger than 10 y.o. since the repercussions of iatrogenic physeal damage would obviously be bigger in this age group. Five out of the 13 showed premature closure and in the remnant eight an open growth plate was observed at follow-up. All patients with open and/or functioning physes after distraction had no local injuries in the growth plate prior to distraction (4 congenital short femora and 4 normal physes). On the contrary, four out of the five cases with prematurely closed physes, had a local physeal damage prior to distraction (3 bony bridges and one non-union), and the remnant was a congenitally short femur. Growth after distraction was difficult to assess in the congenitally short femora but it has been very satisfactory in the 4 cases of previously normal physes (2 benign tumours and 2 femoral shortenings due to hip disorders). In three cases of congenital short femur in pre-teenagers we were able to repeat distraction twice through the same physis, since it had remained open after the first distraction. Conclusions: Physeal premature closure often follows physeal distraction, but not always. The condition of the physis prior to lengthening is an important factor with influence on its viability after distraction


Orthopaedic Proceedings
Vol. 91-B, Issue SUPP_II | Pages 225 - 225
1 May 2009
Hardisty M Akens M Skrinskas T Whyne CM Yee A Toronto O
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Rodents are often used as preclinical models for investigating the biomechanical consequences of spinal pathologies and interventions. Growth plates are present within rat vertebrae throughout life and may alter the vertebral biomechanics. This study investigates the biomechanical response of rat-tail vertebrae to axial compressive loading using μCT imaging and image registration to spatially resolve strain fields. The sixth caudal vertebrae of eight immunocompromised (rnu/rnu) rats were μCT scanned (17.5 ×17.5×17.5μm/pixel) in both loaded (27N-32N axial compression) and unloaded configurations. Image registration was used to calculate strain and displacement fields in the bone due to the applied load by finding a spatial mapping between the two scans. Strain was resolved to varying spatial resolutions; high strain gradient regions, such as the growth plates, were analyzed to higher spatial resolutions. Axial strains calculated by image registration ranged from 2% in tension to 16% in compression with an average axial strain of 1.6% in compression. In seven rats the majority of the strain measured within the vertebrae was concentrated in the growth plate. Very soft growth plates in three specimens resulted in maximum axial strains from 10–16% in compression. The remaining four rats with strain concentrations in the growth plate had maximum axial strains ranging from 2.2%–3.2%. Centrally located strain concentrations of lower magnitudes and more limited spatial extent were observed in the trabecular bone. The majority of the strain within the rat vertebrae was absorbed by the growth plates. The amount of strain within the growth plate is important to consider when interpreting biomechanical data on rat vertebrae. Load application to rodent vertebrae will first compress the growth plate and only following compression of this structure cause significant development of displacement and strains within the trabecular and cortical bone. This insight into the biomechanical response of rat vertebrae is apparent through the application of image registration to analyse vertebral body behaviour; such information would not be evident in analysing preclinical whole vertebral body response using finite element modeling or experimental testing protocols


Orthopaedic Proceedings
Vol. 88-B, Issue SUPP_III | Pages 369 - 369
1 Oct 2006
Bush P Huntley J Macnicol M Hall A
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Introduction: In the growth plate, chondrocyte swelling (hypertrophy) is a crucial event during endochondral ossification and bone lengthening, accounting for ~80% of the increase in bone length (. 1. ,. 3. ). The swelling is dramatic (~10x) and closely regulated. Failure of chondrocyte hypertrophy may underlie the chondrodysplasias of the vertebrate skeleton (. 1. ). However, the mechanisms which control cell swelling are poorly understood although there must be a key role for chondrocyte osmolyte transporters which are sensitive to an increase in cell volume. We have used confocal scanning laser microscopy (CLSM) to study volume regulation by living in situ growth plate chondrocytes at varying degrees of hypertrophy. Methods: Bovine growth plates were taken from the ends of young (~12d) bovine ribs. In situ growth plate chondrocytes at the proliferative through to hypertrophic stages were fluorescently-labelled (calcein-AM; 5μM), imaged (Zeiss CLSM510) and volumes determined quantitatively as described (. 2. ). An acute osmotic challenge (280-140mOsm) was delivered by perfusion to determine volume-regulatory capacity by cells in the various zones. Results: The resting volumes of proliferative and hypertrophic cells were 550±63μm. 3. and 5227±1974μm. 3. respectively. Reducing osmolarity resulted in a rapid (within ~1min) cell swelling, proliferative and hypertrophic chondrocytes increasing in volume by 126±2% and 146±5% (n=5) respectively. Chondrocytes within the proliferative zone then recovered in volume by ~60% over the following 20mins (p=0.04), whereas no volume recovery was detected in hypertrophic cells (p=0.94). Conclusions: For the increase in growth plate chondrocyte volume to produce hypertrophy it is essential that the membrane transporters which normally prevent cell swelling are suppressed, otherwise the increase in volume will be compromised. These results suggest that chondrocyte hypertrophy is associated with reduced activity of the swelling-stimulated osmolyte transporter whereas the pathway is active in proliferating chondrocytes. Changes in the activity of this pathway are likely to be an important component in the control of chondrocyte hypertrophy. It is clear that the contributions of other membrane transporters in mediating chondrocyte swelling must be identified in order to understand the overall hypertrophic process


Orthopaedic Proceedings
Vol. 85-B, Issue SUPP_I | Pages 10 - 10
1 Jan 2003
Roach H Mehta G Oreffo R Cooper C Clarke N
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The growth plates of rapidly growing animals have been studied extensively. Nevertheless, several questions remain unanswered, partly because many events happen simultaneously, especially at the vascular front. Terminal chondrocytes are thought to undergo programmed cell death, but the fate of the cell remnants remains unclear. Are the dying cells released into the vascular space and phagocytosed by macrophages, as one would expect for apoptosis? Or are the cells eliminated prior to opening of the lacunae, leaving empty lacunae? Do all terminal chondrocytes die or do some become bone-forming cells? Rodents maintain a growth plate into old age, long after longitudinal growth has ceased. These stationary growth plates have several features not found in the growth plates of rapidly growing animals and closer study of these features may provide answers to the above questions. Femurs and tibiae from 4–16 week-old and 62–80 week-old rats were decalcified, processed into paraffin, and the morphological changes were documented. Between 4–16 weeks, the heights of the growth plates decreased due to loss of the large hypertrophic chondrocytes, but the various zones were still present. In the aged rats, the growth plates were identifiable as a narrow cartilaginous band with some short columns of inactive cells. The vascular front was irregular, the narrow spicules of primary spongiosa were absent and the much thicker spicules, which are normally seen in secondary spongiosa, directly abutted to the cartilage. Horizontal apposition of bone matrix onto the cartilage edge was frequently present. In addition, the following features were noted. 1) Acellular areas: Nearly all growth plates contained regions of cartilage from which all cells and their lacunae had disappeared. In some cases, these acellular regions stretched from the reserve zone to the vascular front and even persisted as a relatively wide core within the spicules of spongiosa, indicating increased resistance of acellular cartilage to resorption. The absence of cells or cell debris was consistent with an autophagic mode of cell death and subsequent collapse of the lacunae. 2) Remodelling within the growth plate; in some growth plates, large regions of growth plate cartilage had been resorbed and new bone had been laid down in a pattern similar to the remodelling of cortical bone. This suggested that the normal resistance of cartilage to vascular invasion had been lost locally, but was maintained in adjacent non-remodelled regions. 3) Trans-differentiation of chondrocytes to bone-forming cells; extensive new medullary bone formation was noted in the diaphysis of approximately 30% of the aged rats, suggesting that they had received an (unknown) osteogenic stimulus. In these rats, bone matrix was identifiable inside chondrocytic lacunae, and spreading beyond the confines of the lacunae, thus directly replacing growth plate cartilage with bone matrix. The results suggest that i) chondrocytes are capable of self-elimination, perhaps by a mechanism similar to the autophagic cell death that occurs during insect metamorphosis; ii) resorption of cartilage and vascular invasion requires the presence of the viable chondrocytes; and iii) chondrocytes have the capacity to transdifferentiate to bone-forming cells, but only do so when receiving an increased osteogenic stimulus


Orthopaedic Proceedings
Vol. 90-B, Issue SUPP_III | Pages 430 - 430
1 Aug 2008
Zaidma A Zaidman M Korel A Sakharov A Mikhajlovsky M
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Problems of vertebral growth plate metabolism regulation at different stages of ontogenesis are insufficiently covered in the literature. However, the study of function mechanism of provisional cartilage of vertebral growth plate is a practical and theoretical basis of pathogenesis model of idiopathic scoliosis and Scheuermann’s disease both associated with growth disorders. Objective: To investigate the function mechanism of vertebral growth plate structural components during formation and growth. Materials and methods: Fifty vertebral body specimens of children at the age from 1 to 14 years obtained from the forensic medicine department were studied by methods of morphohistochemistry, biochemistry, and ultra-structural analysis. The expression of five proteoglycan genes and their albuminous products was investigated by RT-PCR method. Results: The process of growth represents a sequence of morphogenetic movements ongoing up to the achievement of sexual maturity. But morphofunctional organization and regulation of growth are different in different periods of ontogenesis. Early postnatal growth of vertebral bodies is governed by a radially located zone of growth. The cell population in a just-formed cartilage growth plate is non-uniform: from poorly differentiated chondroblast through the form of highly differentiated ones to degrading chondrocyte. This period of the spine development is characterised by the presence of vessels in provisional cartilage tissue. The concept of “chondro/hematic barrier” suggested and validated by A.M Zaidman explains a conservation of homeostasis at a stage of vertebral bodies differentiation. The process of chondrogenic differentiation of prechondroblasts in the early postnatal period is inducted by the chorda influence. In the late postnatal period (12–14 years) the laws of structural and functional organization of cartilage growth plate of vertebral body remain the same: phenotypic heterogeneity, polarity, and zonality of cells. A metabolic centre of complex architectonics of cartilage tissue is chondroblast. Chondroblast is functioning at the level of chondron which is a functional unit of vertebral growth plate. Chondroblast (chondrocyte) is located in the centre of chondron and surrounded by pericellular matrix presented by diffuse aggrecan molecules, or growth plate aggregates. Due a peculiar architectonics, growth plate molecules have inner spaces comparable in size with Golgi’s vesicles. Metabolites, small molecules, and water freely penetrate through these molecules. Diffuse molecules together with type II thin collagenic fibres, minor collagenes, and structure-forming growth plates perform barrier function. Besides barrier function, diffuse molecules perform information function inside a chondron, forming a kind of information field. Signals of this field are perceived by chondroblast receptors, and the cell gene apparatus expression is carried out through second messengers. Thus, either stimulation of proliferative activity with subsequent differentiation during intensive growth, or interruption of these processes (period of growth delay) occurs. Single chondrons unite into chains in proliferation zones. Cell interaction inside chondron occurs due transmembrane structures, as a contact coordination of functions of cells with inherent high specificity. Concentration of diffuse molecules of growth plate (aggrecan) in proliferation zones is the highest on evidence of histochemical and ultrastructural assays. Besides, diffuse molecules are the short-distance regulators of DNA synthesis the mechanism of action of which is realised through the system of receptors on a cellular membrane. Hence, contact intercellular interactions are one of the mechanisms controlling cell division. These are so-called extracellular factors of chondroblast proliferation regulation. Thus, the process of growth represents a complex two-stage mechanism of proliferation and differentiation of chondroblasts, and adequate osteogenesis. All three processes provide harmonious spine formation, and disturbance of one of them results in pathology development


Orthopaedic Proceedings
Vol. 87-B, Issue SUPP_III | Pages 316 - 316
1 Sep 2005
Gang C Coulton L Lang Y Saleh M
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Introduction and Aims: A previous study showed the inhibitory effect of 30% metaphyseal lengthening on tibial growth (Lee 1993). This study was to investigate the effect of 30% diaphyseal lengthening of tibia on tibial growth plate and growth. Method: 32 immature rabbits were equally divided into two groups: lengthening and sham. A bilateral external fixator was applied to the tibia and a mid-diaphyseal osteotomy performed. The lengthening group had their tibia distracted on the fifth day after the surgery at a rate of 0.4 mm twice daily until the achievement of 30% lengthening. In each group, half were sacrificed at the end of lengthening and another half after an additional five weeks. Standard radiographs were used to measure the lengths of the tibiae from the most proximal part of the intercondylar eminence to the most distal part of the medial malleollus. The actual length gained was measured by subtracting the pre-operative distance from the lengthened distance using the central points of two middle wires in the tibia as reference points. Specimens from the proximal and distal tibia were sectioned longitudinally in the midcoronal plane and the mean growth plate thickness was calculated from several measurements taken at the middle third of both medial and lateral halves of the section. Results: In the sham group, the thickness of the growth plates continued to increase with skeletal development showing an increase in total tibial length compared with the contra-lateral control. In contrast, the lengthening group showed no increase in total tibial length compared to the contra-lateral control, suggesting that the stimulation due to the osteotomy may be matched by an inhibitory effect of 30% lengthening. Conclusion: Thirty percent diaphyseal lengthening of tibia did not change the longitudinal growth of the tibia


Orthopaedic Proceedings
Vol. 90-B, Issue SUPP_II | Pages 390 - 390
1 Jul 2008
Takano H Aizawa T Irie T Yamada N Kokubun S
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In the pubertal growth plate, sex hormones play important roles for the regulation of the proliferation, differentiation, maturation and programmed death of chondrocytes. Many studies have been reported on the regulation of oestrogen in long bone growth, however, some of the mechanisms have remained unclarified to date including its role for cell kinetics in the growth plate chondrocytes. The aim of this study was to clarify the effect of the deficiency of oestrogen on growth plate chondrocytes. We obtained the growth plates of femoral head from the normal and ovariectomized Japanese white rabbits at 10, 15, 20 and 25 weeks. Ovariectomy was performed at 8 weeks. The cell kinetics of chondrocytes as defined by the numbers of proliferating and programmed dying cells was investigated using immunohistological methods. The lengths of the femur were almost same both in the ovariectomised and normal rabbits. The height of the growth plate was larger in the former. The total number of chondrocytes in the ovariectomised rabbits was less than that of normal rabbits of the same age. Immunostaining of proliferating cell nucleous antigen (PCNA) showed a decrease number of proliferating chondrocytes and that of caspase-3 indicated a little increased number of apoptotic chondrocytes. Oestrogen regulates endochondral bone formation through several pathways. It directly binds oestrogen receptor alpha and beta, and the former accelerates longitudinal bone growth whereas the latter represses it. Another pathway is through the GH-IGF-I axis: it closely interacts with GH and IGF-I for the control of longitudinal bone growth. In addition, there might be other mediators including transforming growth factor-beta, other IGFs and still unknown paracrine or auto-crine factors as IHH PTHrP. Our study suggests that in the rabbit growth plate during puberty, oestrogen mainly acts through the GH-IGF-I axis since its defi-ciency declined the proliferating ability of chondrocytes, which led the decrease of the number of chondrocytes


Orthopaedic Proceedings
Vol. 99-B, Issue SUPP_5 | Pages 47 - 47
1 Mar 2017
Nakamura T Niki Y Nagai K Sassa T Heldreth M
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Introduction. Design evolution of total knee arthroplasty (TKA) has improved implant durability and clinical outcomes. However, it has been reported that some patients have limited satisfaction with their operated knees [1]. In view of better patient satisfaction, there have been growing interests in anatomically aligned TKA. The anatomically aligned TKA technique aims to replicate natural joint line of the patients [2][3]. However, restoration of natural joint line may be difficult for the knees with severe deformity, as their joint alignment with respect to bony landmarks at a time of surgery may be critically different from their pre-diseased state. The purpose of this study is to investigate alignment of the tibial growth plate with respect to tibial anatomical landmarks for possible application in estimation of pre-diseased joint alignment. Methods. Three-dimensional tibial models were created from CT scans of 22 healthy Japanese knees (M7:F15, Age 31.0±12.6 years) using Mimics (Materialise NV, Leuven, Belgium). The mid-sagittal plane of the tibia was defined by medial margin of the tibial tuberosity, origin of the PCL and center of the foot joint. The tibial plateau (or joint line plane) was determined by following three points; a dwell point of aligned femur on lateral tibial articular surface, and two points at anterior and posterior rim of medial tibial articular surface defined within sagittal plane that coincide with dwell point of femur on medial tibia. All measurements were made with respect to the mid-sagittal plane. The shape of the tibial growth plate (GP) was extracted using Livewire function and mask editing tools of Mimics. To determine 3D orientation of the GP, moment of inertia axes were calculated for the 3D model. The inertia axes were also determined for medial and lateral half of the GP (Figure 1). Results. Tibial plateau (TP) had 2.38±1.78 degrees of varus and 11.37±3.76 degrees of posterior inclination. In coronal view, the GP axis was in varus alignment to the normal axis of the TP by 3.29±1.45 degrees. The shape of the GP is found to be different for medial and lateral half. The posterior inclination of the medial half tends to follow the TP, while the lateral half is twisted anteriorly (Figure 2). The GP medial half was in 5.03±2.89 degrees valgus and 1.62±2.37 degrees anteriorly inclined relative to the TP. The GP lateral half was in 10.38±2.62 degrees varus and 18.11±3.79 degrees anteriorly inclined relative to the TP. Discussion. The results from 22 healthy knees suggested that the tibial growth plate is aligned to tibial plateau in varus orientations with relatively small deviations. Distinctive shape difference for medial and lateral half of the growth plate was also observed. Limitation of this study is a number of subjects available for the analysis. Future study should consider inclusion of arthritic knees with various levels of deformities. For figures/tables, please contact authors directly.


Orthopaedic Proceedings
Vol. 85-B, Issue SUPP_III | Pages 266 - 267
1 Mar 2003
Aykut U Yazici M Gedikoglu G Kandemir U Aksoy M Surat A
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Introduction: Prior to skeletal maturity temporary hemiepiphyseal stapling is a treatment method for angular deformities of long bones. The purpose of this study is to investigate the effects of temporary hemiepiphyseal stapling on the bone geometry and histology of physis. Materials & Methods: Proximal medial epipyseal stapling of the right tibia were done in 46 New Zealand rabbits. 23 of them were euthanized at the end of 3 weeks. For the remaining 23 rabbits staples were fixed subperiostally (group A) in 11, and extraperiosteally (group B) in 12 rabbits. After 3 weeks the staples removed and the rabbits were euthanized at the end of 6 weeks. Bromodeoxyuridine used to evaluate cellular activity of the growth plate. Radiographs utilized for bone alignment. Results: The articular surface-diaphysis angle was significantly increased at the end three weeks when compared to controls (27.7° vs. −1.5°, p:0.001). Cellular activity was decreased but preserved in the stapled tibias. At the end of six weeks while the angular deformity was worsening in group A 22.9° vs. 35.6°, p:0.001) it was improving in group B (23.2 ° vs. 14.6°, p:0.001). Bone tissue bridging the growth plate was noted in group A. Cellular activity in the group B was higher than group A at the end of six weeks. Conclusion: Hemiepiphyseal stapling causes decreased cellular activity at the growth plate, which leads to angulation. With removal of staples, increased cellular activity at the growth plate results in the improvement of the deformity if staples were inserted extraperiosteally. Temporary extraperiosteal hemiepiphyseal stapling could be used as a safe and effective method for treatment of angular deformities prior to skeletal maturity


Orthopaedic Proceedings
Vol. 88-B, Issue SUPP_I | Pages 125 - 125
1 Mar 2006
Kasis A Pacheco R Saleh M
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Aim: To review the outcome following growth plate arrest in distal femur and proximal tibia of different aetiology in adults. Materials and methods: We have reviewed, retrospectively, eight adult patients with lower leg deformity in the distal femur and proximal tibia, as a sequelae of growth plate arrest of different aetiology. These patients underwent tibial and femoral, correction and lengthening. The total number was 8 patients, there were 6 male and 2 female, with an average age of 22.8 years (17–34.8) The average follow up was 32.9 months (7.9–51.4). Results: Four patients had growth plate arrest following trauma (two patients were involved in road traffic accidents, one had Salter-Harris type V fracture of the proximal tibia and one had sport injury), two patients had iatrogenic growth plate arrest after internal fixation of tibial spine in one patient and after internal fixation of a popliteal muscle rupture in the other, one patient had Osgood Schlater disease, one patient had childhood osteomyelitis and one unknown pathology. The average shortening was 34.8 mm (8–60), the average maximum deformity in any one plane was 19.8 degree (6–40). All the patient underwent corrective surgery and lengthening, five patients had Sheffield Ring Fixator, two had Limb Reconstruction System and one had percutaneous osteotomy on Albizzia nail. The patients who underwent SRF and LRS stayed in the frame for an average 258 days (150–435). The residual leg length discrepancy was 5.5 mm (0–12). There was three grade one complications, three grade two complications, and one patient had grade IV complication following compartment syndrome. Four patients had grade two pin site infection and three patients had grade one. Conclusion: Growth plate arrest of the distal femur and proximal tibia can cause severe deformity and shortening of the lower limb in adult, and this deformity is amenable to correction in the end of growth using different techniques. We used Sheffield ring fixator in complex cases, to address both deformities and lengthening, while other techniques were used in less complex cases


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXIII | Pages 122 - 122
1 May 2012
Xian C McCarty R Gronthos S Chung R Zannettino A Foster B
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Introduction and aims. Growth plate cartilage is responsible for bone growth in children. Injury to growth plate can often lead to faulty bony repair and bone growth deformities, which represents a significant clinical problem. This work aims to develop a biological treatment. Methods. Recent studies using rabbit models to investigate the efficacy of bone marrow mesenchymal stem cells (MSC) to promote cartilage regeneration and prevent bone defects following growth plate injury have shown promise. However, translational studies in large animal models (such as lambs), which more closely resemble the human condition, are lacking. Results. Very recently, our labs have shown that ovine bone marrow MSC are multipotential and can form cartilage-like tissue when transplanted into mice. However, using a growth plate injury model in lambs, analogous to those described in the rabbit, autologous marrow MSC seeded into gelatine scaffold containing chondrogenic factor TGF-1, failed to promote growth plate regeneration. T o date, no large animal studies have reported successful regeneration of injured growth plate cartilage using MSC highlighting the possibility that ex vivo expanded MSC may not represent a viable cellular therapy for growth plate injury repair. In addition, using a growth plate injury repair model in young rats, our studies have also focused on understanding mechanisms of the faulty repair and identifying potential targets for enhancing growth plate regeneration using endogenous progenitor cells. We have observed that bony repair of injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses involving both intramembranous and endochondral ossification mechanisms. We have observed infiltration of mesenchymal progenitor cells into the injury site, some of which have the potential to differentiate to osteoblasts or chondrocytes and contribute to the bony repair of the injured growth plate. Conclusion. This presentation will focus on our studies examining the efficacy of ex vivo expanded autologous MSC to enhance growth plate regeneration in the ovine model and work using a rat model aimed at identifying potential targets for enhancing cartilage regeneration by mobilising endogenous stromal progenitor cells


Orthopaedic Proceedings
Vol. 86-B, Issue SUPP_II | Pages 196 - 196
1 Feb 2004
Antapur P Gent E Clarke NMP Taylor GR
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Aim: Unicameral bone cysts are difficult to treat as partial cyst healing may reverse and it may be difficult to assess between active and latent types. Materials and Methods: 19 patients with unicameral bone cysts were reviewed with a mean age of 8.5 years (16 males and 3 females). These 19 patients were reviewed over a period of fifteen years and all except one, had an active cyst abutting the growth plate. 18 cases were treated with curettage and burring using a dental burr and six cases were treated with elastic nailing. 12 cases were treated with bone marrow injection either alone or in combination with the above procedures. 2 cases were treated with steroid injections. No cases were bone grafted. Results: The best results were obtained with curettage and burring of the lining of the cysts. Bone marrow injection alone did not produce resolution of any of the cysts. Migration of the cysts away from the growth plate in response to treatment (conversion from active to latent status) was predictive of successful treatment with no symptoms and no further fractures, irrespective of the age of the patient. Conclusion: Successful treatment of unicameral bone cysts can be predicted by the appearance of normal bone formation by the physis and subsequent migration of the cyst away from the growth plate. The association of successful treatment and conversion to latency of the cyst has not previously been reported