Bruce K. Foster

Statistical analysis of the incidence of physeal injuries.

The incidence of physeal injuries in nearly 2,000 bony injuries was 18%. They were commoner in adolescents and specifically more frequent in the upper limbs. The incidence of growth arrest was just over 1%, whereas the incidence of serious complication was <1%. The prognosis depends more on the site than the Salter-Harris classification. The proximal tibia is a common site for growth disturbance.

Roles of Wnt Signalling in Bone Growth, Remodelling, Skeletal Disorders and Fracture Repair

Wnt signalling has an essential role in regulating bone formation and remodelling during embryonic development and throughout postnatal and adult life. Specifically, Wnt signalling regulates bone formation by controlling embryonic cartilage development and postnatal chondrogenesis, osteoblastogenesis, osteoclastogenesis, endochondral bone formation, and bone remodelling. Abnormalities in the function of Wnt genes give rise to or contribute to the development of several pathological bone conditions, including abnormal bone mass, osteosarcomas and bone loss in multiple myeloma. Furthermore, Wnt signalling is activated during bone fracture repair and plays a crucial role in regulating bone regeneration. J. Cell. Physiol. 215: 578–587, 2008.

Characterisation and developmental potential of ovine bone marrow derived mesenchymal stem cells

Since discovery, significant interest has been generated in the potential application of mesenchymal stem cells or multipotential stromal cells (MSC) for tissue regeneration and repair, due to their proliferative and multipotential capabilities. Although the sheep is often used as a large animal model for translating potential therapies for musculoskeletal injury and repair, the characteristics of MSC from ovine bone marrow have been inadequately described. Histological and gene expression studies have previously shown that ovine MSC share similar properties with human and rodents MSC, including their capacity for clonogenic growth and multiple stromal lineage differentiation. In the present study, ovine bone marrow derived MSCs positively express cell surface markers associated with MSC such as CD29, CD44 and CD166, and lacked expression of CD14, CD31 and CD45. Under serum‐deprived conditions, proliferation of MSC occurred in response to EGF, PDGF, FGF‐2, IGF‐1 and most significantly TGF‐α. While subcutaneous transplantation of ovine MSC in association with a ceramic HA/TCP carrier into immunocomprimised mice resulted in ectopic osteogenesis, adipogenesis and haematopoietic‐support activity, transplantation of these cells within a gelatin sponge displayed partial chondrogenesis. The comprehensive characterisation of ovine MSC described herein provides important information for future translational studies involving ovine MSC. J. Cell. Physiol. 219: 324–333, 2009.

TNF‐α Mediates p38 MAP Kinase Activation and Negatively Regulates Bone Formation at the Injured Growth Plate in Rats

TNF‐α is known to inhibit osteoblast differentiation in vitro and yet it is essential for bone fracture repair. Roles of TNF‐α in the bony repair of injured growth plate were examined in young rats treated with a TNF‐α antagonist. The results show that TNF‐α mediates p38 activation, which influences the recruitment, proliferation, and osteoblast differentiation of mesenchymal cells and negatively regulates bone formation at the injured growth plate.

Difficult supracondylar elbow fractures in children: analysis of percutaneous pinning technique.

After treatment with two lateral percutaneous pins, 80 children with grade II-III supracondylar elbow fractures were reviewed. The result was good in 55 patients (68%) and was the same for extension- and flexion-type injuries. These patients had less than 10 degrees change in carrying angle and less than 20 degrees total change in range of motion. This method eliminates risk of iatrogenic injury to the ulnar nerve but is technically very demanding. Redisplacement, joint penetration, and damage to the capitellar side of growth plate can be avoided only by positioning the pins divergently.

Roles of neutrophil‐mediated inflammatory response in the bony repair of injured growth plate cartilage in young rats

Injured growth plate cartilage is often repaired by bony tissue, resulting in impaired bone growth in children. Previously, injury‐induced, initial inflammatory response was shown to be an acute inflammatory event containing predominantly neutrophils. To examine potential roles of neutrophils in the bony repair, a neutrophil‐neutralizing antiserum or control normal serum was administered systemically in rats with growth plate injury. The inflammatory response was found temporally associated with increased expression of neutrophil chemotactic chemokine cytokine‐induced neutrophil chemoattractant‐1 and cytokines TNF‐α and IL‐1β. Following the inflammatory response, mesenchymal infiltration, chondrogenic and osteogenic responses, and bony repair were observed at the injury site. Neutrophil reduction did not significantly affect infiltration of other inflammatory cells and expression of TNF‐α and IL‐1β and growth factors, platelet‐derived growth factor‐B and TGF‐β1, at the injured growth plate on Day 1 and had no effects on mesenchymal infiltration on Day 4. By Day 10, however, there was a significant reduction in proportion of mesenchymal repair tissue but an increase (although statistically insignificant) in bony trabeculae and a decrease in cartilaginous tissue within the injury site. Consistently, in antiserum‐treated rats, there was an increase in expression of osteoblastic differentiation transcription factor cbf‐α1 and bone matrix protein osteocalcin and a decrease in chondrogenic transcription factor Sox‐9 and cartilage matrix collagen‐II in the injured growth plate. These results suggest that injury‐induced, neutrophil‐mediated inflammatory response appears to suppress mesenchymal cell osteoblastic differentiation but enhance chondrogenic differentiation, and thus, it may be involved in regulating downstream chondrogenic and osteogenic events for growth plate bony repair.

Repair of injured articular and growth plate cartilage using mesenchymal stem cells and chondrogenic gene therapy.

Injuries to the articular cartilage and growth plate are significant clinical problems due to their limited ability to regenerate themselves. Despite progress in orthopedic surgery and some success in development of chondrocyte transplantation treatment and in early tissue-engineering work, cartilage regeneration using a biological approach still remains a great challenge. In the last 15 years, researchers have made significant advances and tremendous progress in exploring the potentials of mesenchymal stem cells (MSCs) in cartilage repair. These include (a) identifying readily available sources of and devising appropriate techniques for isolation and culture expansion of MSCs that have good chondrogenic differentiation capability, (b) discovering appropriate growth factors (such as TGF-beta, IGF-I, BMPs, and FGF-2) that promote MSC chondrogenic differentiation, (c) identifying or engineering biological or artificial matrix scaffolds as carriers for MSCs and growth factors for their transplantation and defect filling. In addition, representing another new perspective for cartilage repair is the successful demonstration of gene therapy with chondrogenic growth factors or inflammatory inhibitors (either individually or in combination), either directly to the cartilage tissue or mediated through transducing and transplanting cultured chondrocytes, MSCs or other mesenchymal cells. However, despite these rapid pre-clinical advances and some success in engineering cartilage-like tissue and in repairing articular and growth plate cartilage, challenges of their clinical translation remain. To achieve clinical effectiveness, safety, and practicality of using MSCs for cartilage repair, one critical investigation will be to examine the optimal combination of MSC sources, growth factor cocktails, and supporting carrier matrixes. As more insights are acquired into the critical factors regulating MSC migration, proliferation and chondrogenic differentiation both ex vivo and in vivo, it will be possible clinically to orchestrate desirable repair of injured articular and growth plate cartilage, either by transplanting ex vivo expanded MSCs or MSCs with genetic modifications, or by mobilising endogenous MSCs from adjacent source tissues such as synovium, bone marrow, or trabecular bone.

Remodelling after pinning for slipped capital femoral epiphysis

We assessed 70 hips at an average of 7.1 years after pinning for slipped upper femoral epiphysis to determine the frequency of remodelling, what factors influence it and its effect on the clinical outcome. Remodelling was defined by a new classification of the anterior femoral head-neck profile as seen on the lateral radiograph. Remodelling occurred in 50% of hips with a head-shaft angle of 30 degrees or more; the probability of remodelling was significantly less the greater the degree of slip, but was significantly increased if the triradiate cartilage was open at the time of presentation. We found no significant effect for age, sex, weight or length of symptoms. The range of internal rotation was significantly greater in those hips that remodelled. We support the treatment of moderate slips in skeletally immature patients by pinning in situ, since the probability of satisfactory remodelling was 75% for slips of 40 degrees or less.

Methotrexate chemotherapy reduces osteogenesis but increases adipogenic potential in the bone marrow

Intensive use of cancer chemotherapy is increasingly linked with long‐term skeletal side effects such as osteopenia, osteoporosis and fractures. However, cellular mechanisms by which chemotherapy affects bone integrity remain unclear. Methotrexate (MTX), used commonly as an anti‐metabolite, is known to cause bone defects. To study the pathophysiology of MTX‐induced bone loss, we examined effects on bone and marrow fat volume, population size and differentiation potential of bone marrow stromal cells (BMSC) in adult rats following chemotherapy for a short‐term (five once‐daily doses at 0.75 mg/kg) or a 6‐week term (5 doses at 0.65 mg/kg + 9 days rest + 1.3 mg/kg twice weekly for 4 weeks). Histological analyses revealed that both acute and chronic MTX treatments caused a significant decrease in metaphyseal trabecular bone volume and an increase in marrow adipose mass. In the acute model, proliferation of BMSCs significantly decreased on days 3–9, and consistently the stromal progenitor cell population as assessed by CFU‐F formation was significantly reduced on day 9. Ex vivo differentiation assays showed that while the osteogenic potential of isolated BMSCs was significantly reduced, their adipogenic capacity was markedly increased on day 9. Consistently, RT‐PCR gene expression analyses showed osteogenic transcription factors Runx2 and Osterix (Osx) to be decreased but adipogenic genes PPARγ and FABP4 up‐regulated on days 6 and 9 in the stromal population. These findings indicate that MTX chemotherapy reduces the bone marrow stromal progenitor cell population and induces a switch in differentiation potential towards adipogenesis at the expense of osteogenesis, resulting in osteopenia and marrow adiposity. J. Cell. Physiol. 227: 909–918, 2012.

Late diagnosis of congenital dislocation of the hip and presence of a screening programme: South Australian population-based study

BACKGROUND The Medical Research Council Working Party on Congenital Dislocation of the Hip have reported an ascertainment-adjusted incidence of a first operative procedure for congenital dislocation of the hip (CDH) of 0.78 per 1000 livebirths, which is similar to the incidence of CDH before the start of the UK screening programme. The report showed that CDH had not been detected by routine screening before age 3 months in 70% of children reported to the national orthopaedic surveillance scheme. This report raised concerns about the merit of screening at birth for CDH. We aimed to find out the incidence of an operative procedure for CDH in the first 5 years of life among children born in South Australia between 1988 and 1993, and the proportion of these patients that were detected at age 3 months or older. METHODS The states database for inpatient separations between January, 1988, and April, 1998 was searched. Case records were examined for the age and circumstances of diagnosis, and type of operative procedures. Prevalence rates of CDH were obtained from the South Australian Birth Defects Register, which receives notifications from a statutory perinatal data collection of birth defects detected at birth and subsequent voluntary notifications for children up to age 5 years. FINDINGS Of the 55 children born in South Australia between 1988 and 1993 identified as having non-teratological CDH and operative procedures, only 22 (40%) had been diagnosed at age 3 months or older. 18 had an open reduction of the hip joint or osteotomy, or both, and the remainder had arthrograms, closed reductions, and/or tenotomy. The prevalence of non-teratological CDH in children was 7.74 per 1000 livebirths. The incidence of surgery for CDH in the first 5 years of life was 0.46 per 1000 livebirths (95% CI 0.34-0.59) and only 0.19 per 1000 livebirths (0.11-0.26) for those diagnosed late (age 3 months or older). These children diagnosed late represented 2.4% of all known cases of CDH. INTERPRETATION Only 2.4% of known cases of CDH in children born in South Australia had been detected late and required surgery. These results show that a screening programme for CDH can be successful, contrary to the findings of the UK Medical Research Council Working Party.