Introduction: Following an Australian study on the incidence of scoliosis in a population of short-statured children treated with human growth hormone (conducted during 2001–2002), it was determined that the only risk factor for the presence of idiopathic scoliosis was having Turner/another syndrome. The 30% incidence in Turner syndrome was noted to be much higher than previously reported (11–12%). The aim of this study is to determine the incidence of scoliosis in a group of growth hormone-treated and non-treated Turner Syndrome subjects who attended the International Turner Syndrome Society meeting in Sydney, Australia in July 2003 and to correlate the results with the Australian 2001–2002 results. Methods: 88 subjects were clinically examined for the presence and severity of idiopathic scoliosis. Their ages ranged from 11 to 60 years. All subjects provided information regarding previous growth hormone and/or oestrogen administration. Anthropometric data including sitting and standing height and arm span was also collated on this cohort. Results: 13 of 46 (28.3%) subjects who had no growth hormone treatment were found to have scoliosis. Five of 42 (12%) subjects who were growth hormone treated were found to have scoliosis. 12 curves were thoracic, five were thoracolumbar and one was lumbar. The 13 subjects with scoliosis and no growth hormone treatment had curves between10 and 20° Cobb angle. Three growth hormone-treated subjects had curves of 10°, one had a curve of 30° and the last subject had already undergone scoliosis surgery. Combining the results of this study with the three Australian States study from 2001–2002, 18 of 87 (21%) growth hormone-treated Turner syndrome subjects have idiopathic scoliosis. 13 of 46 (28%) non-growth hormone-treated Turner syndrome subjects also have idiopathic scoliosis. Of the total 133 subjects in this cohort, 31 (23%) have idiopathic scoliosis. Discussion: The incidence of idiopathic scoliosis in Turner syndrome appears to have been understated in previous studies. Data from this study would indicate that treating children who have Turner syndrome with adjuvant human growth hormone does not appear to result in a greater incidence or severity of idiopathic scoliosis. In this relatively small study, two of five children who had previous growth hormone treatment developed larger curves, one requiring corrective scoliosis surgery

Introduction: Retrospective reports of adverse events following growth hormone administration to short-statured children indicate that the incidence of scoliosis is elevated, largely due to the higher incidence of scoliosis in Turner/other syndromes within the group. The aims of this study are to analyse risk factors for scoliosis in these children. Methods: Data on 184 of 267 (65%) current and recent Australian children from the Australian OZGROW program was collected in 2001/2002 (from three Australian States). This included medical records (including past history of known scoliosis), growth charts, timing of growth hormone and oestrogen administration and the presence and severity of scoliosis from clinical examination. Growth hormone dosage was controlled by Australian Health Department guidelines. Standard oestrogen dosage was similar for all pubertal girls. The cohort was noted to comprise many varying syndromes, some of whom were pituitary hormone deficient. Potential risk factors for the development of scoliosis were statistically analysed. Results: Of 45 subjects with Turner Syndrome, 13 (30%) have idiopathic scoliosis and 2 have a hemi-vertebra. Of the other 139 subjects, 15 have scoliosis but 11 have syndromes which would normally be associated with scoliosis. Therefore, the incidence of idiopathic scoliosis in the remaining 128 subjects is 3.1% (4/128), which is within the normal population range. All 4 have mild scoliosis < 20 degrees. For the 139 subjects with idiopathic short stature or a specific syndrome, the age of commencement and total amount of growth hormone and/or oestrogen did not affect the degree of scoliosis. Discussion: Having Turner Syndrome was the only variable identified as a risk factor for having scoliosis (p< .001). The incidence of scoliosis in growth hormone treated Turner Syndrome subjects is much larger than previously reported (11–12%). 1,. 2. To the authors’ knowledge, this is the first report derived from non-retrospective data on the incidence of scoliosis in a growth hormone–treated Turner Syndrome population. This stimulated the next study looking at the incidence of scoliosis in growth hormone-treated and non-growth hormone-treated subjects with Turner Syndrome

A one-year-8-month-old girl who received radiotherapy and chemotheraphy after excision of embryonal rhabdomyosarcoma from left labium majus pudendi developed slipped capital femoral epiphysis (SCFE) over right hip when she was 9 years old. After mild limp had been noted for 6 months she was then referred to pediatric orthopedic surgeon and two Knowles pins were used to fix the slipping. The second case was a 17-year-old girl with Turner syndrome. SCFE developed during the growth hormone therapy and it was treated with percutaneous pinning with two cannnulated screws. The possibility of developing SCFE should always be kept in mind when treating and following these particular cases to avoid delay of diagnosis

Aims. The assessment of the potential pathological influence of Growth Hormone (hGH), Testosterone, Estradiol, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone in the development of SCFE and the re-evaluation of the Harris theory (increased quotient of hGH/sex hormones in patients suffering from SCFE). Methods. Nineteen patients in total were included in the study. Fourteen patients (7 boys, 7 girls, 16 hips) suffering from SCFE during the proceeding of this study, formed group ‘A’. Another 5 patients (4 boys, 1 girl), that had been treated for SCFE a few years before the study, formed group ‘B’. We measured serum hGH, FSH, LH, Testosterone and Estradiol levels. Furthermore we checked all necessary anthropometrical and clinical characteristics (age, height & weight, sexual maturation, grade of slipping). Results. Thirty six out of 95 in total measurements (37,9%) revealed pathological values. The majority of group A patients had pathological values (43% of measurements). The Harris theory seems to be true in 7 out of 19 in total patients: 5 group A patients (2 boys and 3 girls) and 2 group B patients (1 boy and 1 girl). Conclusions. We believe that a temporary (?) disorder or imbalance of hGH and sexhormones, under the possible influence of FSH and LH (along with other etiologic factors) during the early years of adolescence, may play a potentially significant role in the development of SCFE

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

Introduction and Aims: SHOX haploinsufficiency presents with Turner syndrome dysmorphic skeletal features – micrognathia (60%), cubitus valgus (47%), high-arched palate (25%) and Madelung deformity (7%). Idiopathic scoliosis is also present in 11% of Turner syndrome. This clinical observation and radiological study explores the possibility of SHOX haploinsufficiency expression in the scoliotic spine in Turner syndrome. Method: Turner syndrome presents a mesomelic short stature, thought to result from growth plate dysmorphism, presumably from SHOX gene haploinsufficiency. Forty-five Turner syndrome subjects on the Australian Growth Hormone program were clinically examined for the presence of idiopathic scoliosis. Of another 88 Turner syndrome subjects similarly examined, 46 had received growth hormone and 42 had never received growth hormone. Kosowicz (1959) and Preger (1968) noted irregular vertebral endplates of scoliotic spines in Turner syndrome subjects. This may imply dysmorphic vertebral growth plates. A spinal MRI and plain imaging study of idiopathic scoliosis with/without Turner syndrome was undertaken to examine for vertebral growth plate abnormalities. Results: This study again demonstrates plain radiographic presence of irregular vertebral endplates of scoliotic spines in Turner syndrome. Spine MR imaging in Turner syndrome failed to clearly demonstrate the growth plates but demonstrated wedge-shaped distal vertebrae in the curve. Similar MR findings were noted in another 20 subjects with various causes of scoliosis. Wedged-shaped intervertebral discs were also noted, but are thought to be secondary changes. Of 87 Turner syndrome subjects from growth hormone programs, 18 (21%) were found to have idiopathic scoliosis. Thirteen of another 46 (28%) subjects who had never received growth hormone were also noted to have idiopathic scoliosis, indicating a combined incidence of 23%. These results contrast with Lippe (1991) and Kim (2001), who noted an incidence of 11% of 163 and 12% of 43 idiopathic scoliosis in Turner syndrome from retrospective observation. However, the incidence of scoliosis (41%) from the radiographic studies of Kosowicz (4/22) and Preger (19/34) is much greater than even the incidence noted clinically from this study. Conclusion: SHOX haploinsufficiency expression is not yet described in Turner syndrome scoliotic spines, although it has been described in the distal radius (Munns, 2001) in Madelung deformity. The incidence of idiopathic scoliosis in Turner syndrome appears to be much larger than previously recognised, signalling a probable dysmorphic vertebral growth plate cause

Purpose of the study: Determine the prevalence and course of spinal deformations in Willi-Prader syndrome and assess the effect of treatment with growth hormone. Analyze outcome after conservative and surgical treatments. Material and methods: We reviewed the files of 51 patients with Willi-Prader syndrome proven genetically. Spinal deformations were classed according to the SRS system. Body mass index (BMI) was determined and correlated with age and administration of growth hormone. Statistical analysis used the coefficient of correlation and the chi-square test to search for correlations between qualitative variables. Results: There were 37 girls and 24 boys, mean age at last follow-up 10.7±6.7 years. The prevalence of scoliosis was 52% and varied according to genotype. The prevalence of scoliosis deformations was higher in patients aged over ten years (p< 0.01). The prevalence of scoliosis was greater in female patients. Patients with BMI< 25 had a significantly lower risk of scoliosis. Treatment with growth hormone was associated with a significant decrease in risk of scoliosis. Among scoliosis patients, ten had a main curvature < 15° and were monitored. Eleven had a curvature > 15° (31±11°) and were treated with a corset. Five had a curvature > 50° and trunk imbalance and were treated surgically. Four of these patients developed serious complications. Discussion: Scoliosis deformation is frequent in Willi-Prader syndrome. Weight control is very important and BMI should be maintained below 25 to limit the risk of scoliosis. Treatment with growth hormone helps limit BMI and thus the risk of scoliosis. For major deformations, surgical treatment is indicated but at the risk of serious postoperative complications

Introduction Delayed puberty and delayed skeletal maturation have been implicated as risk factors for the progression of idiopathic scoliosis. Genetic defects (Turner syndrome) and hypothalamic- pituitary disorders are known causes of delayed puberty. Although it is recognized that the incidence of idiopathic scoliosis is elevated in Turner syndrome, human studies regarding the incidence/severity of scoliosis in children with suprasellar, hypothalamic region and pituitary tumours/ disorders is deficient. Methods A medical records search in five Australian states for suprasellar, hypothalamic region and pituitary tumours/disorders was performed. Identified patients underwent clinical or radiological evaluation for scoliosis. Pathology varied from suprasellar-hypothalamic region tumours, pan-hypopituitarism, pituitary tumours and growth hormone deficiency as well as a craniopharyngioma, arachnoid cyst, retinoblastoma and encephalocele. Results Of 23 identified patients, ten are female. Mean age at presentation was 8.4 years. Three have right thoracic scoliosis with a Cobb angle less than 20 degrees. Two are males; one with pituitary hormone deficiency and the other with Cushing’s disease treated with radiotherapy. The only female is on a growth hormone treatment program for idiopathic growth hormone deficiency. Discussion The only female with scoliosis was 12 years old. Delayed puberty could not be linked to either male with scoliosis. Although the incidence of idiopathic scoliosis in this cohort is greater than expected from Caucasian population studies (2–3%), the male preponderance is unusual. No relationship between delayed skeletal maturation and idiopathic scoliosis could be established

Summary. Arginine supplementation is helpful in treatment of osteoporosis. Introduction. Nitric oxide (NO) is a short-lived free radical involved in several biological processes as a bioregulator and as a second messenger. It inhibits osteoclastic bone resorption in vitro and regulates bone remodeling. Zolendronic acid has been established as a treatment for post menopausal osteoporosis. Study was done to compare the efficacy of Nitic oxide donor (L-arginine) with that of Zolendronic acid for the treatment of osteoporosis. Method. The study was not designed to compare these two drugs against a placebo, because the beneficial effects of Zolendronic acid in treatment of osteoporosis are well established. Institutional Review Board approvals were obtained. One hundred patients of osteoporosis having T score of −2.5 or more, were randomised to receive L-arginine) or Zolendronic acid. All patients received 1.0 g of calcium and 400 IU of vitamin D supplementation per day. In addition Group I patients received L-arginine (2 gm.) per day while Group II patients received zoledronic acid 5 mg i.v. over 15 min. Patient were followed at regular intervals clinically, by biochemical investigations and at one year for DEXA scan. Results. Patients in both groups improved clinically and bio-chemically over one year period. T score on DEXA scan at one year showed improvement in bone density. Average pretreatment T score was −3.65 in group I and −3.52 in group II. At one year followup average T score was −2.9 in group I and −2.6 in group II. Difference was not statistically significant. Discussion. Oral administration of L-arginine in pharmacological doses induces growth hormone and insulin like growth factor-1 responses and stimulates nitric oxide synthesis. Growth hormone and insulin like growth factor-1 are important mediator of bone turnover and osteoblastic bone formation. While nitric oxide is potent inhibitor of osteoclastic bone resorption because of this dual effect on physiological regulator of bone remodeling. L-arginine could potentially increase bone formation over bone resorption and consequently increase bone mass. Oral supplementation of L-arginine may be novel strategy in prevention and treatment of osteoporosis

Background. Acromegaly, which stems from high level of serum growth hormone secreted by a benign tumour in the anterior pituitary gland, is likely to cause severe peripheral joint pains due to hypertrophic changes in such joints. Recently, the life expectancy of such patients has been improved and more patients with acromegaly have undergone joint surgeries to mitigate joint pain and malfunctions. However, little is known about to what extent surgical procedures can improve the joint functions of acromegalic patients compared to non-acromegalic cases. Methods. First, we qualitatively analysed prognosis of total hip arthroplasty (THA) of acromegalic patients by investigating 11 cases in which direct anterior approach (DAA) THAs were performed to 8 acromegalic patients in our hospital between 2012 and 2015. Second, we quantitatively compared the functional prognosis of the 11 cases with that of 107 non-acromegalic cases. Technically, to control the difference in age, sex, height, and weight between the two patient groups, we first identified a model that could predict 3month-/6month-/12month-functional prognosis in the control cases. We estimated differences in functional outcomes between the two groups by calculating how accurately the control-case-based model could predict the prognosis of the acromegalic cases. Results. In the qualitative analysis, we found that compared to the control, the most acromegalic cases had atypically advanced degenerative arthritides with osteophytes and enthesophytes proliferations. In addition, some cases showed other signs, such as flattering of femoral head and arthritis with slight osteophytes. Regarding surgical procedures, acromegalic cases were likely to require longer operation time and larger amounts of blood loss compared to the control. In the quantitative analysis, we first identified a model in which age and body height could predict the functional prognosis of DAA THA in the non-acromegalic cases (F[2,104] = 6.7, P = 0.0017). We then found that the actual functional outcomes of the acromegalic cases were not significantly different from those predicted by this control-case-based model (P = 0.18). Conclusions. The qualitative analysis shows the atypical joint structures and resultant prolonged operation time and blood loss in the acromegalic cases. However, the quantitative analysis could not find significant differences in prognosis between the acromegalic and non-acromegalic cases. Although these observations and analyses need to be examined in studies with large sample sizes, this work suggests that functional outcomes of DAA THA to acromegalic patients can be comparable to that to non-acromegalic patients

Eight children developed osteochondroma (OS) at a mean of 88 months, after hematopoietic stem cell transplantation (HSCT). The mean age at HSCT was 56 months (12-84). This represents a cumulative incidence of 20% among patients less than 18 years of age transplanted from 1981 to 1997. These eight patients underwent allogeneic (n=2) of autologous (n=6) transplantation for either acute leukemia (n=6) or neuroblastoma (n=2) after a conditioning regimen including total body irradiation (n=7) or a combination of Busulfan and Cyclophosphamide.Multiple OS were indentified in seven patients and a solitary OS in one. Locations included: clavicle (2), ribs (2), superior iliac epiphysis (1), metaphy-sis of the distal femur (2), distal (2) and proximal (1) tibia, proximal humerus (1), distal radii (3), scapula (3), proximal metaphysis of the proximal phalanges of the fingers (2) and parietal bone (1). OS were asymptomatic in four children. Eight lesions in five patients were resected and all were benign. No recurrence occured.Four children received growth hormone before diagnosis of OS, but there was no clinical, radiological or histological difference between those who did not. Univariate analysis showed an increased rate associated only with autolo-gous HSCT, with a 31,7% probability of a new OS et 12 years after HSCT.Ostoechondroma should be added to the other adverse effects of HSCT in children

Purpose. To define the orthopaedic problems associated with pseudoachondroplasia (PSACH) and their functional impact. Methods. We reviewed the medical records of 12 consecutive patients presenting to our unit. Radiographic analysis of deformity included assessment of mechanical axis and dysplasia at hip, knee and ankle measured by acetabular index (AI), Reimer's migration percentage (MP), neck-shaft angle, distal lateral femoral (aDFLA) and proximal (mMPTA) and distal tibial angles. The paediatric/adolescent PODCI questionnaires and the SF36 were used to assess quality of life issues. Results. 12 patients (9 female) were reviewed at median age 18yrs (range 12-43yrs). Most symptoms related to walking tolerance, joint discomfort and deformity: 9 patients had genu varum, 7 tibial torsion, 2 patella instability and 3 significant low back pain. All patients had hip dysplasia. 10 had medial displacement of the mechanical axis, with a mean mDFLA 105 deg (88 -128) and mMPTA 75deg (51-90). 2 patients have been treated only with growth hormone; 10 patients have undergone a total of 9 distal femoral, 19 proximal tibial and 2 supramalleolar osteotomies. 6 procedures were performed using an external fixator. 7 limb segments have been treated by guided growth and in all these cases alignment has improved. One patient has had bilateral hip arthroplasties (age 29), a second patient has had bilateral patellectomies. These 10 patients have undergone a mean 3.8 operative procedures on a mean 2.4 occasions. Patients scored less well than their peer groups in all domains of the PODCI assessment. All have maintained some independent mobility. Conclusions. PSACH is a severe skeletal dysplasia with deformity at all levels of the lower limb affecting patient satisfaction and quality of life. Knee deformities are those which most frequently require surgical intervention. Significance. The genetic defect in PSACH differs from that in achondroplasia, joint degeneration is more common and maintenance of limb alignment is essential

Introduction. Problematic bone defects are encountered regularly in orthopaedic practice particularly in fracture non-union, revision hip and knee arthroplasty, following bone tumour excision and in spinal fusion surgery. At present the optimal source of graft to ‘fill’ these defects is autologous bone but this has significant drawbacks including harvest site morbidity and limited quantities. Bone marrow has been proposed as the main source of osteogenic stem cells for the tissue-engineered cell therapy approach to bone defect management. Such cells constitute a minute proportion of the total marrow cell population and their isolation and expansion is a time consuming and expensive strategy. In this study we investigated human bone marrow stem cells as a potential treatment of bone defect by looking at variability in patient osteogenic cell populations as a function of patient differences. We produced a model to predict which patients would be more suited to cell based therapies and propose possible methods for improving the quality of grafts. Methods. Bone marrow was harvested from 30 patients undergoing elective total hip replacement surgery in Musgrave Park Hospital, Belfast (12 males, 18 females, age range 52-82 years). The osteogenic stem cell fraction was cultured and subsequently analysed using colony forming efficiency assays, flow cytometry, fluorescence activated cell sorting and proteomics. Results. The number and proliferative capacity of osteogenic stem cells varied markedly between patients. Statistical analysis revealed significantly better osteogenic capacity in:. male patients. samples in which the growth hormone Fibroblastic Growth Factor-2 was added to culture medium. patients who used the cholesterol lowering agent simvastatin. Patient use of inhaled steroids and NSAIDs were found to have detrimental effects. A statistical model to predict marrow profiles based on these variables was produced. Conclusions. Stem cell based tissue engineering represents the future of the treatment of bone defect. This study provides evidence that inter-patient variability in marrow cell colony forming and proliferation ability can in some way be explained by patient associated factors. Using this knowledge, we can identify which patients would be best suited to this method of treatment and propose techniques for enhancement of their graft profiles

Osteosarcoma rarely affects young children. To determine the clinical characteristics and the prognosis of this cancer in children of less than 5 years at diagnosis, we retrospectively analysed medical records of these patients treated in French centers between 1980 and 2007. A centralised histological review was carried out. Fifteen patients were studied. Long bones were involved in 14 cases. Metastases at diagnosis were observed in 40% of patients. Histologic type was 74% osteoblastic. In 3 cases (20%) tumours occurred on a particular background (tall constitutional size, treatment with growth hormone and pregnancy induced by clomiphene). One child had a second cancer 13 years after the first diagnosis. Twelve children received pre-operative chemotherapy including high dose methotrexate: 5 of them had progressive disease; only 36% had good histological response (less than 10% viable cells). Limb salvage surgery was performed in six cases (40%). Chemotherapy was well tolerated in most patients. A one-year-old child developed a severe late convulsant encephalopathy with lesions of the white substance that could be due to methotrexate despite adjustment of doses to his weight. The functional recovery of the three analysable children who underwent limb salvage surgery is uneven and shows frequent mechanical or infectious complications (2 to 5 reinterventions per patients). First complete remission (CR) was obtained in 12 children, six of them relapsed. With a median follow-up of 15 years, six are alive in CR, six died of disease (40%), two were lost to follow-up and one has stable disease with metastasis. This study shows that osteosarcoma seems to be more aggressive in children under five years of age. Surgical management remains difficult in this population. Prospective studies are still needed to confirm these observations

From January 2003 a long term follow-up project started for adult patients treated in our Centre for cancer in pediatric age, to evaluate late effects of therapy. For all patients a personalized follow-up was scheduled (time, function-tests, etc). We analyzed 24 cases of bone tumors: 14 osteosarcoma (OS) and 10 Ewing’s sarcoma (ES). Median age at diagnosis was 13 years (range 11–18) for OS patients, 11.6 years (range 6–18) for ES; 50% males in both groups. All patients were treated according current CNR/ISG-protocols: all OS cases underwent surgery; in 5/10 ES patients local treatment was surgery, in 5/10 radiotherapy; 7/24 received hematopoietic stem cells transplantation (HSCT). Median age at evaluation is respectively 26.5 years (range 18.7–34) and 23.5 (range 21.6–32); median follow-up is 13 years (range 6–22) and 13.7 (range 6.7–22.3). Cardiovascular function is normal in all OS cases; 3/10 ES patients developed asymptomatic ejection fraction reduction, currently not treated. One OS patient underwent bilateral thoracotomy and HSCT for multiple metastases at diagnosis and had a mild lung function alteration. One OS patient developed mild chronic kidney disease, one ES nephrolithiasis. Liver function is normal in all cases. Height velocity and final height are normal in 10/14 OS and 9/10 ES patients; in remaining 5/24 no growth hormone secretion deficit was found. One OS patient developed primitive hypothyroidism and one OS benign thyroid nodule with partial thyroidectomy; one patient multifocal papillary thyroid carcinoma with total thyroidectomy at 11 years from diagnosis of ES. Spermatogenesis deficit is a common find (5/7 OS and 5/5 ES male patients); one female treated with HSCT and radiotherapy for ES pelvic relapse has primitive hypogonadism. No other hypothalamo-hypophyseal-adrenocortical system hormones deficit was found. We reported no significant neuropsychological alterations nor employment problems: 20/24 patients have a job, 4/24 are students. Three OS females have children

Purpose: Hyaline cartilage lesion in a large weight bearing joint can lead, if not treated, to damage of the subchondral bone. Since cartilage tissue does not heal spontaneously, nor can it regenerate, joint functional restitution is based on temporary biological solutions. The only promising approach for recovering damaged joint and avoid its eventual deterioration is to restore the genuine surfacing of hyaline cartilage. Methods: We have developed a novel primary chondrocytes culture based on a unique source of cartilage cells whereby a gradual collagenase separation yield a homogenous chondrocyte population, which unlike other cartilage source-derived cells preserve the capability of spontaneous differentiation into cartilage forming cells. Results: Following a short period of intensive proliferation, the cells start to differentiate into polygonal shaped cells, expressing Cbfa1-the skeletal tissues specific transcription factor, type II collagen and cartilage proteoglycan; thus producing a genuine hyaline cartilage. The cultured chondrocytes also preserve their responsiveness toward local and systemic factors such as growth hormone, insulin, PTH and IGF1. Since, cartilage is an immuno-privileged tissue; non- autologous cartilage sources may also be successfully transplanted. We have shown that mourine and porcine-derived cells injected into rats afflicted (AIA) joints replenish the articular lesion with no signs of WBC infiltration. Since, prior to differentiation, these cells undergo an intensive proliferation phase they can also be transfected. We have also shown that osteoprotegerin (OPG)-firstly known for its activity as RANK ligand decoy receptor, has direct ameliorative effects on cartilage development. We have shown that OPG transfected chondrocytes preserve their typical morphological and functional features. Conclusions: This model of primary chondrocyte culture, develop authentic resemblance to hyaline (surfacing) cartilage with similar physical and mechanical properties of the original tissue. These cells can be successfully transplanted into damaged joint of a foreign host. Hence, we propose that these primary spontaneously-differentiating chondrocytes, from non autologous source- can be suitable for replenishment of articular lesions as well as vehicle for local application of beneficial cytokines like OPG

Introduction: The highest goal after meniscus damage is the preservation of the meniscus, which is often not possible due to the bad healing of meniscus lesions in the avascular zone. Therefore, the goal of our investigations was the analysis of expression of different angiogenic factors, growth hormones and cytokines in human meniscus cells (fibrochondrocytes). The mutual influence of the fibrochondrocytes by endothelial cell cocultures was analyzed, in order to examine the molecular bases of the healing of meniscus tears in vascularized zones more exactly. For this purpose, commercially available HUVEC [human umbilical vein endothelial cells] were used as well established and stable endothelial cell model. Material and Methods: Meniscal fibrochondrocytes were expanded in DMEM medium enriched with antibiotics and 10 % FCS. Cocultures of mensical cells and HUVEC were incubated in transwells over four and twelve days, separated by a semipermeable membrane. The expression of Angiopoietin-1, Angiopoietin-2, End-ostatin, VEGF, SMAD-4, Thrombospondin-1, Aggrecan, Biglycan, Fibronectin, Vimentin, Connexin-43, IL-1β, iNOS, MMP-1, MMP-3, MMP-13, collagen-I, -II, -III, -VI, X, and -XVIII were examined by RT-PCR and immunhistochemistry in fibrochondrocytes in the comparison to cultures without endothelial coculture. A proliferation assay was used to investigate the mitotic activity in the coculture compared to the control culture after 4 and 12 days. Results: In presence of HUVEC, meniscal fibrochon-drocytes expressed the following factors at rates comparable to cells w/o HUVECS: Angiopoietin-1, Angiopoietin-2, VEGF, SMAD-4, Aggrecan, Biglycan, Fibronectin, Vimentin, Connexin-43, iNOS, MMP-1, MMP-3, MMP-13, Thrombostatin-1, collagen-I, -II, -III, -VI, X, and -XVIII. In contrast, expression of end-ostatin (5.1-fold ± 1.2, p< 0.01) and IL-1β (10.3-fold ± 2.3, p< 0.003) were expressed significantly higher in the coculture when compared to the individual cell cultures. The proliferation rate of HUVEC was significantly decreased in coculture when compared to controls: 22 % after 7 days and 35 % after 14 days (p< 0.001). Discussion/ Conclusion: We were able to cultivate and characterize human fibrochondrocytes from menisci of the knee joint. We could show that coculture of meniscus cells with endothelial cells revealed an increased expression of the anti-angiogenetic factor endostatin and the pro-inflammatory IL-1β. This suggests that meniscus cells are trying to inhibit proliferation of endothelial cells in their neigbourhood, which implicates huge problems in the research field of neoangiogenisis and tissue engineering in meniscus tissue for new healing methods after meniscus trauma

Cartilaginous tissues such as articular cartilage and the intervertebral disc are called upon to function under very high pressures which they can do, thanks to the very special properties of their two major components, viz., the proteoglycans (PG) and collagen. The PG, a flexible polyelectrolyte of high fixed charge density has a high osmotic pressure and therefore a tendency to imbibe water and maintain tissue turgor while the collagen mesh, with its good tensile properties, prevents undue swelling, thus enabling the proteoglycan-water mixture to exist as a concentrated solution. Moreover, by resisting instantaneous deformation, the collagen network ensures the dimensional stability of cartilage. The combination of the two components enables a cartilaginous tissue to exhibit flexibility and to withstand tensile stresses as well as high compressive loads. Moreover, cartilage is an avascular tissue, hence the transport of nutrients and different substrates is controlled by the properties of the matrix. In addition to common nutrients, various regulatory substances, such as growth hormones and cytokines, also have to reach the cell. These substances are often required in extremely small amounts which, however, need to be rigorously controlled. This again, depends on transport through the extracellular space. At the same time, metabolic waste products are secreted by the cells into the matrix and have to pass through the latter in order to reach the synovial fluid for removal from the joint space. The same must happen to matrix macromolecules degraded in the course of normal turnover, whether the degradation happens intra- or extracellularly. Finally, macromolecules, newly synthesized by the cells, are secreted into the matrix and must move through it before being assembled at some distance from the cell. The concentration of a solute within the matrix, apart from being an important factor in determining the rate of transport, is also able to modify the properties of the matrix itself. Thus, ionic concentrations are largely responsible for determining the level of the osmotic pressure within the cartilage matrix in general, and in the immediate environment of the cell in particular. The osmotic pressure of the matrix, in turn, is responsible for the resistance of cartilage to fluid loss and hence to compressive stresses. Together with the hydraulic permeability of the pore space, it is also an important determinant of the rate of fluid movement out of and into the tissue. In addition, the high ionic concentration and osmotic pressure in the immediate environment of the chondrocyte have been shown to affect their synthetic processes

Aims

Avascular femoral head necrosis in the context of gymnastics is a rare but serious complication, appearing similar to Perthes’ disease but occurring later during adolescence. Based on 3D CT animations, we propose repetitive impact between the main supplying vessels on the posterolateral femoral neck and the posterior acetabular wall in hyperextension and external rotation as a possible cause of direct vascular damage, and subsequent femoral head necrosis in three adolescent female gymnasts we are reporting on.

Despite biomechanical well established implants and improved operation techniques we still have a too high rate of complications in orthopaedic and trauma surgery like non-union, implant loosening or implant associated infections. The development of bioactive implants could improve the clinical outcome. Growth factors are important regulators of bone metabolism. During fracture healing many growth factors or cytokines were locally released at the facture site. In several studies, different growth factors demonstrated osteoinductive and fracture stimulating properties. In vitro and in vivo studies showed a stimulating effect of Insulin-like growth factor-I (IGF-I), Transforming growth factor-A71 (TGF-A71) and Bone morphogenetic protein-2 (BMP-2) on osteo- and chondrogenetic cells. The exact effectiveness and the interaction of these growth factors during fracture healing is not known so far. Further, the local application of these factors for therapeutically use in fracture treatment is still a problem. A biodegradable poly(D,L-lactide)-coating of implants allows the local and controlled release of incorporated growth factors directly at the fracture site. The coated implant serves on the one hand for fracture stabilization and on the other hand as a drug delivery system. The coating has a high mechanical stability. The incorporated growths factors remain biologically active in the coating and were released in a sustained and controlled manner. To investigate the effect of locally released growth factors IGF-I, TGF-A71 and BMP-2 and the carrier PDLLA on fracture healing, standardised closed fracture models were developed with a close relationship to clinical situation. Further, possible local and systemic side effects were analysed. The results demonstrated a significantly higher stimulating effect of IGF-I on fracture healing compared to TGF-A71. The combined application of both growth factors showed a synergistic effect on the mechanical stability and callus remodeling compared to single treatment. The local release of BMP-2 also enhanced fracture healing significantly – comparable to combination of IGF-I and TGF-A71. However, a higher rate of mineralisation was measurable outside the fracture region using BMP-2 in a rat fracture model. Using a large animal model on pigs with a 1 mm osteotomy gap, the effectiveness of locally released growths factors could be confirmed. Further, the PDLLA-coating without any incorporated growth factors demonstrated a significantly effect on healing processes in both models. These investigations showed, that the local release of growth factors from PDLLA coated implants significantly stimulate fracture healing without any local or systemic side effects. Comparing systemic with local stimulation techniques, we found an improvement of fracture healing by systemic administration of growth hormone and local application of IGF-I and TGF-A71. However, the combined use of both simulation techniques did not lead to a further increase of healing processes. Investigations on the effectiveness and the interaction of growth factors during fracture healing demonstrated an dramatic effect in the early phases of healing processes. The growth factors stimulate the differentiation of osteoblasts with a higher production of collagen I in vitro and increase osteogenesis and vascularisation of the fracture callus in vivo. Further applications of the coating technology are the use of PDLLA and growth factor coated cages for the stimulation of intervertebral fusion and the use of PDLLA and Gentamicin coated implants in order to prevent implant associated infections. The first patients with open tibia fractures were treated with PDLLA and Gentamicin coated IM nails