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Early life influences on skeletal health
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Abstracts / Bone 45 (2009) S46–S52
effectiveness of this approach are not yet available. New surgical treatments, such as arthrodiastasis (distraction) of the hip joint and “core decompression” of the femoral head, are being tried in some centers. The effectiveness of these treatments in preventing femoral head deformity is also unknown at this time. doi:10.1016/j.bone.2009.04.010
P9 Limb reconstruction in children using distraction osteogenesis Reggie C. Hamdy Orthopaedics Department, McGill University, Canada Distraction Osteogenesis (DO) is a form of in-vivo bone tissue engineering technique where an osteotomy of a long bone is performed followed by the application of an external fixator to the proximal and distal ends of the bone. Gradual and controlled distraction of the bone fragments is then performed and new bone is formed in the distraction gap. This technique is used worldwide in the reconstruction of musculoskeletal deformities, limb lengthening and in the replacement of massive bone loss. However, the long period of time the external fixator has to be kept on until the newly formed bone in the distraction gap consolidates may lead to numerous medical, social and financial problems for the patient, the family and the health care institution. The main focus of our research has been on various methods to accelerate the consolidation of this newly formed bone so that the external fixator can be removed earlier. We have shown that local application of recombinant Bone Morphogenetic Protein 7 (BMP7) accelerates bone formation in a rabbit DO model. However, large doses of BMPs have to be used in order to obtain a positive response. In order to decrease the amount of exogenously applied BMPs we have developed – in collaboration with the Biomedical Engineering Department at McGill University – a nanoparticle delivery system. Another alternative to the use of exogenous BMPs is the manipulation of the endogenous BMP pathway. We have previously shown that BMP antagonists are expressed during DO and therefore, we are studying various methods to block BMP antagonists in the distraction gap to increase the efficiency of the endogenous BMPs. Hence, by positively manipulating the endogenous BMP pathway, we may be able to avoid exogenous BMP applications. doi:10.1016/j.bone.2009.04.011
P10 Human skeletal (mesenchymal) stem cells lineage fate regulation Moustapha Kassem Endocrinology and Metabolism, University Hospital of Odense, Denmark Director Molecular Endocrinology Lab (KMEB) Medical Biotechnology Center, University of Southern Denmark, Denmark Human bone marrow skeletal (mesenchymal) stem cells (hMSC) are capable of differentiation into several mesodermal-type lineage cells including osteoblasts and adipocytes. The signaling pathways controlling hMSC differentiation outcome are partially understood. Our laboratory has identified Dlk1/pref1 as a novel factor regulating human mesenchymal stem cell (hMSC) differentiation. Dlk1 (delta-like 1 protein, also named, Pref-1) encodes a trans-membrane protein with six EGF-like repeats and belongs to Notch/Serrate/delta family. We have demonstrated that over-expression of Dlk1 in hMSC led to inhibition of their differentiation into osteoblasts, adipocytes and chondrocytes. Using DNA microarray approach, we found that the inhibitory effects of Dlk1/Pref-1 on hMSC differentiation were associated with increased production of a large number of inflammatory cytokines by hMSC
suggesting a role for the control of stem cell niche composition. To investigate the in vivo effect of dlk1/FA1 on bone remodelling, we examined three models of gene modified mice: mice expressing high serum levels of circulating dlk1/FA1 protein, using hydrodynamic gene transfer procedure, osteoblast-specific-Dlk1 over-expressing mice (Col3.6/Dlk1) and Dlk1-deficient mice. Results from these studies will be presented at the meeting. Our data demonstrate that Dlk1/FA1 is a novel regulator of MSC transition from proliferation to differentiation and an example of developmental molecule that acquires a novel function regulating tissue homeostasis in adult organism. doi:10.1016/j.bone.2009.04.012
P11 Early life influences on skeletal health Cyrus Cooper MRC Epidemiology Resource Centre, University of Southampton; and Norman Collisson Chair of Musculoskeletal Science, University of Oxford, UK Osteoporosis is a skeletal disease characterised by low bone mass and susceptibility to fracture. Preventive strategies against osteoporotic fracture can be targeted throughout the life course. Although there is evidence to suggest that peak bone mass is inherited, current genetic markers are able to explain only a small proportion of the variation in individual bone mass or fracture risk. Evidence has begun to accrue that fracture risk might be modified by environmental influences during intrauterine or early postnatal life: (1) Epidemiological studies which confirm that subjects who are born light and whose growth falters in the first year of postnatal life, have significantly lower bone size and mineral content, at age 60 to 75 years; (2) Cohort studies demonstrating that subsequent lower trajectories of childhood growth are associated with an increased risk of hip fracture among such men and women; (3) Detailed physiological studies of candidate endocrine systems which might be programmed have shown that birthweight and growth in infancy alter the functional settings of the GH/IGF-1, and vitamin d/PTH axes; (4) Studies characterising the nutrition, body build and lifestyle of pregnant women which relate these to the bone mass of their newborn offspring, have identified a number of important determinants of reduced fetal mineral accrual (maternal smoking, low maternal fat stores and maternal vitamin D deficiency, intense levels of weightbearing physical activity in late pregnancy). Follow-up studies of randomised controlled trials of vitamin D supplementation in infancy suggest persisting benefits in adolescence and young adulthood. These data suggest that undernutrition and other adverse influences arising in fetal life or immediately after birth have a permanent effect on body structure, physiology and metabolism, which might independently influence the later risk of osteoporotic fracture. doi:10.1016/j.bone.2009.04.013
P12 What has ALSPAC told us about children’s bones? Jon Tobias Academic Rheumatology, Department of Clinical Science at North Bristol, University of Bristol, UK The Avon Longitudinal Study of Parents and Children (ALSPAC) comprises 14,000 pregnant mothers and off-spring recruited in 1990–1, of whom around 7000 children underwent DXA scans from age 10. We used this cohort to examine environmental, genetic and endocrine influences on skeletal development acting at different stages in childhood. In terms of prenatal influences, background sunlight exposure during the last trimester, ascertained from meteorological
Abstracts / Bone 45 (2009) S46–S52
effectiveness of this approach are not yet available. New surgical treatments, such as arthrodiastasis (distraction) of the hip joint and “core decompression” of the femoral head, are being tried in some centers. The effectiveness of these treatments in preventing femoral head deformity is also unknown at this time. doi:10.1016/j.bone.2009.04.010
P9 Limb reconstruction in children using distraction osteogenesis Reggie C. Hamdy Orthopaedics Department, McGill University, Canada Distraction Osteogenesis (DO) is a form of in-vivo bone tissue engineering technique where an osteotomy of a long bone is performed followed by the application of an external fixator to the proximal and distal ends of the bone. Gradual and controlled distraction of the bone fragments is then performed and new bone is formed in the distraction gap. This technique is used worldwide in the reconstruction of musculoskeletal deformities, limb lengthening and in the replacement of massive bone loss. However, the long period of time the external fixator has to be kept on until the newly formed bone in the distraction gap consolidates may lead to numerous medical, social and financial problems for the patient, the family and the health care institution. The main focus of our research has been on various methods to accelerate the consolidation of this newly formed bone so that the external fixator can be removed earlier. We have shown that local application of recombinant Bone Morphogenetic Protein 7 (BMP7) accelerates bone formation in a rabbit DO model. However, large doses of BMPs have to be used in order to obtain a positive response. In order to decrease the amount of exogenously applied BMPs we have developed – in collaboration with the Biomedical Engineering Department at McGill University – a nanoparticle delivery system. Another alternative to the use of exogenous BMPs is the manipulation of the endogenous BMP pathway. We have previously shown that BMP antagonists are expressed during DO and therefore, we are studying various methods to block BMP antagonists in the distraction gap to increase the efficiency of the endogenous BMPs. Hence, by positively manipulating the endogenous BMP pathway, we may be able to avoid exogenous BMP applications. doi:10.1016/j.bone.2009.04.011
P10 Human skeletal (mesenchymal) stem cells lineage fate regulation Moustapha Kassem Endocrinology and Metabolism, University Hospital of Odense, Denmark Director Molecular Endocrinology Lab (KMEB) Medical Biotechnology Center, University of Southern Denmark, Denmark Human bone marrow skeletal (mesenchymal) stem cells (hMSC) are capable of differentiation into several mesodermal-type lineage cells including osteoblasts and adipocytes. The signaling pathways controlling hMSC differentiation outcome are partially understood. Our laboratory has identified Dlk1/pref1 as a novel factor regulating human mesenchymal stem cell (hMSC) differentiation. Dlk1 (delta-like 1 protein, also named, Pref-1) encodes a trans-membrane protein with six EGF-like repeats and belongs to Notch/Serrate/delta family. We have demonstrated that over-expression of Dlk1 in hMSC led to inhibition of their differentiation into osteoblasts, adipocytes and chondrocytes. Using DNA microarray approach, we found that the inhibitory effects of Dlk1/Pref-1 on hMSC differentiation were associated with increased production of a large number of inflammatory cytokines by hMSC
suggesting a role for the control of stem cell niche composition. To investigate the in vivo effect of dlk1/FA1 on bone remodelling, we examined three models of gene modified mice: mice expressing high serum levels of circulating dlk1/FA1 protein, using hydrodynamic gene transfer procedure, osteoblast-specific-Dlk1 over-expressing mice (Col3.6/Dlk1) and Dlk1-deficient mice. Results from these studies will be presented at the meeting. Our data demonstrate that Dlk1/FA1 is a novel regulator of MSC transition from proliferation to differentiation and an example of developmental molecule that acquires a novel function regulating tissue homeostasis in adult organism. doi:10.1016/j.bone.2009.04.012
P11 Early life influences on skeletal health Cyrus Cooper MRC Epidemiology Resource Centre, University of Southampton; and Norman Collisson Chair of Musculoskeletal Science, University of Oxford, UK Osteoporosis is a skeletal disease characterised by low bone mass and susceptibility to fracture. Preventive strategies against osteoporotic fracture can be targeted throughout the life course. Although there is evidence to suggest that peak bone mass is inherited, current genetic markers are able to explain only a small proportion of the variation in individual bone mass or fracture risk. Evidence has begun to accrue that fracture risk might be modified by environmental influences during intrauterine or early postnatal life: (1) Epidemiological studies which confirm that subjects who are born light and whose growth falters in the first year of postnatal life, have significantly lower bone size and mineral content, at age 60 to 75 years; (2) Cohort studies demonstrating that subsequent lower trajectories of childhood growth are associated with an increased risk of hip fracture among such men and women; (3) Detailed physiological studies of candidate endocrine systems which might be programmed have shown that birthweight and growth in infancy alter the functional settings of the GH/IGF-1, and vitamin d/PTH axes; (4) Studies characterising the nutrition, body build and lifestyle of pregnant women which relate these to the bone mass of their newborn offspring, have identified a number of important determinants of reduced fetal mineral accrual (maternal smoking, low maternal fat stores and maternal vitamin D deficiency, intense levels of weightbearing physical activity in late pregnancy). Follow-up studies of randomised controlled trials of vitamin D supplementation in infancy suggest persisting benefits in adolescence and young adulthood. These data suggest that undernutrition and other adverse influences arising in fetal life or immediately after birth have a permanent effect on body structure, physiology and metabolism, which might independently influence the later risk of osteoporotic fracture. doi:10.1016/j.bone.2009.04.013
P12 What has ALSPAC told us about children’s bones? Jon Tobias Academic Rheumatology, Department of Clinical Science at North Bristol, University of Bristol, UK The Avon Longitudinal Study of Parents and Children (ALSPAC) comprises 14,000 pregnant mothers and off-spring recruited in 1990–1, of whom around 7000 children underwent DXA scans from age 10. We used this cohort to examine environmental, genetic and endocrine influences on skeletal development acting at different stages in childhood. In terms of prenatal influences, background sunlight exposure during the last trimester, ascertained from meteorological