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TGF-beta and bone matrix material properties
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Abstracts / Bone 44 (2009) S18–S55
deformation corresponded with the appearance of several large-strain deformation bands across the specimen [G. Benecke et al, J. Mater. Res., in press (2009)]. (1) P. Fratzl et al, J. Mater. Chem. 14 (2004) 2115. (2) H. S. Gupta et al, Proc. Natl. Acad. Sci. 103 (2006) 17741. (3) H. S. Gupta et al, J. Roy. Soc. Interface 4 (2007) 277. (4) G. Benecke et al, J. Mater. Res., in press (2009). doi:10.1016/j.bone.2009.01.084
047 TGF-beta and bone matrix material properties T. Alliston Orthopaedic Surgery, UCSF, San Francisco, CA, United States The material properties of extracellular matrices contribute to a tissue's mechanical integrity and are a source of cues that direct cellular behavior. Given their importance to the biological and structural function of a tissue, these material properties are tissuespecific and carefully defined. Even within the skeleton, bone matrix material properties are anatomically distinct, such that the bone matrix of the cochlea is harder than the bone matrix of the femur or calvarial bone. However, the mechanisms that establish a tissue's distinctive material properties remain unclear. Transforming growth factor beta (TGF-β) has emerged as a growth factor that can regulate the elastic modulus of bone, skin, and other extracellular matrices during development. Inhibition of TGF-β signaling, through the TGF-β receptor complex and its downstream effector, Smad3, increased bone matrix elastic modulus, as well as several other bone properties. TGF-β inhibits osteoblast differentiation by Smad3-dependent repression of Runx2. In the same manner, TGF-β targets the function of Runx2 to define bone matrix elastic modulus and hardness as assessed by nanoindentation. Downstream transcriptional targets of TGF-β and Runx2 that are responsible for the differences in these material properties remain under investigation. Whether changes in bone matrix material properties could be achieved only by developmental alteration of TGF-β function remained unclear. To examine the role of TGF-β in the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-β type I receptor (TβRI) kinase on bone mass, architecture and material properties. Inhibition of TβRI function had both anabolic and anti-catabolic effects that increased bone mass, improved trabecular architecture, and increased bone matrix mineral concentration and material properties. The coordinate regulation of multiple bone parameters by inhibition of TGF-β function also resulted in increased bone fracture resistance, suggesting the therapeutic potential for targeting the TGF-β pathway to treat conditions of skeletal fragility. doi:10.1016/j.bone.2009.01.085
048 Strategies for preventing falls in the elderly J.C.T. Close Geriatric Medicine, Prince of Wales Hospital, Randwick, NSW, Australia The prevention of falls and fall related fracture is an ongoing challenge for many countries across the world. Over the last 14 years there have been approximately 120 RCTs looking at whether it is possible to prevent falls and fall related injury in older people. A reasonably robust evidence base now exists to support a number of approaches to falls prevention including exercise, OT home assessment, cataract extraction, medication modification and a multifaceted approach to prevention. The evidence also suggests that approaches
need to be population specific and therefore knowledge of the literature is required to ensure individuals are offered an intervention for which there is an anticipated benefit. Prevention of fall related fracture in older people is a key priority area for many health care services given the associated costs both to the individual and to the health care system. Addressing bone health in isolation of falls risk factors is unlikely to represent the most cost-effective approach to fracture prevention and there is an imperative for those interested in fracture prevention to develop models of care that address both the bone related and fall related factors for fracture. doi:10.1016/j.bone.2009.01.086
049 Bone microarchitecture and fracture risk M.L. Bouxsein Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, United States Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microstructural deterioration of bone tissue with a consequent increase in bone fragility. The importance of trabecular and cortical bone microstructure to bone strength is well documented. Therefore evaluation of both microarchitecture and BMD may improve estimation of the risk of fracture. However, until recently the only way to assess bone microarchitecture was via histomorphometric analysis of iliac crest biopsies. Recently, noninvasive imaging methods, including high-resolution peripheral quantitative computed tomography (hr-pQCT) and high-resolution magnetic resonance imaging (hr-MRI), that allow in vivo 3D assessment of bone microstructure at peripheral skeletal sites have been developed. In addition, multi-detector QCT and flat-panel CT are being used to assess trabecular and cortical bone architecture. Recent studies indicate that in postmenopausal women, vertebral and non-vertebral fractures are associated with low volumetric bone density, architectural alterations of trabecular and cortical bone. These alterations are partially independent of aBMD assessed by DXA, suggesting that assessment of bone microarchitecture in vivo may provide improved sensitivity and/or specificity in identifying individuals at greatest risk for fracture. With a goal of outlining the potential clinical utility of these imaging modalities, this lecture will review the clinical studies with focus on three areas — use of bone architecture measurements to: 1) gain new insight to the patterns of age- and disease-related bone deterioration; 2) identify individuals at greatest risk for fracture; and 3) monitor treatment efficacy. The use of micro-finite element analysis based on hr-pQCT images will also be reviewed. The current data provide strong rationale for prospective studies to determine the utility of assessing microarchitecture for predicting the risk of osteoporotic fractures, as well as monitoring disease progression and the response to treatments. doi:10.1016/j.bone.2009.01.087
050 Vitamin D, falls and fractures — What's new? F.H. Anderson Healthy Ageing Group, University of Southampton, Southampton, United Kingdom Vitamin D deficiency and insufficiency are strongly associated with osteoporosis and fracture. Vitamin D also seems important to
Abstracts / Bone 44 (2009) S18–S55
deformation corresponded with the appearance of several large-strain deformation bands across the specimen [G. Benecke et al, J. Mater. Res., in press (2009)]. (1) P. Fratzl et al, J. Mater. Chem. 14 (2004) 2115. (2) H. S. Gupta et al, Proc. Natl. Acad. Sci. 103 (2006) 17741. (3) H. S. Gupta et al, J. Roy. Soc. Interface 4 (2007) 277. (4) G. Benecke et al, J. Mater. Res., in press (2009). doi:10.1016/j.bone.2009.01.084
047 TGF-beta and bone matrix material properties T. Alliston Orthopaedic Surgery, UCSF, San Francisco, CA, United States The material properties of extracellular matrices contribute to a tissue's mechanical integrity and are a source of cues that direct cellular behavior. Given their importance to the biological and structural function of a tissue, these material properties are tissuespecific and carefully defined. Even within the skeleton, bone matrix material properties are anatomically distinct, such that the bone matrix of the cochlea is harder than the bone matrix of the femur or calvarial bone. However, the mechanisms that establish a tissue's distinctive material properties remain unclear. Transforming growth factor beta (TGF-β) has emerged as a growth factor that can regulate the elastic modulus of bone, skin, and other extracellular matrices during development. Inhibition of TGF-β signaling, through the TGF-β receptor complex and its downstream effector, Smad3, increased bone matrix elastic modulus, as well as several other bone properties. TGF-β inhibits osteoblast differentiation by Smad3-dependent repression of Runx2. In the same manner, TGF-β targets the function of Runx2 to define bone matrix elastic modulus and hardness as assessed by nanoindentation. Downstream transcriptional targets of TGF-β and Runx2 that are responsible for the differences in these material properties remain under investigation. Whether changes in bone matrix material properties could be achieved only by developmental alteration of TGF-β function remained unclear. To examine the role of TGF-β in the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-β type I receptor (TβRI) kinase on bone mass, architecture and material properties. Inhibition of TβRI function had both anabolic and anti-catabolic effects that increased bone mass, improved trabecular architecture, and increased bone matrix mineral concentration and material properties. The coordinate regulation of multiple bone parameters by inhibition of TGF-β function also resulted in increased bone fracture resistance, suggesting the therapeutic potential for targeting the TGF-β pathway to treat conditions of skeletal fragility. doi:10.1016/j.bone.2009.01.085
048 Strategies for preventing falls in the elderly J.C.T. Close Geriatric Medicine, Prince of Wales Hospital, Randwick, NSW, Australia The prevention of falls and fall related fracture is an ongoing challenge for many countries across the world. Over the last 14 years there have been approximately 120 RCTs looking at whether it is possible to prevent falls and fall related injury in older people. A reasonably robust evidence base now exists to support a number of approaches to falls prevention including exercise, OT home assessment, cataract extraction, medication modification and a multifaceted approach to prevention. The evidence also suggests that approaches
need to be population specific and therefore knowledge of the literature is required to ensure individuals are offered an intervention for which there is an anticipated benefit. Prevention of fall related fracture in older people is a key priority area for many health care services given the associated costs both to the individual and to the health care system. Addressing bone health in isolation of falls risk factors is unlikely to represent the most cost-effective approach to fracture prevention and there is an imperative for those interested in fracture prevention to develop models of care that address both the bone related and fall related factors for fracture. doi:10.1016/j.bone.2009.01.086
049 Bone microarchitecture and fracture risk M.L. Bouxsein Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, United States Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microstructural deterioration of bone tissue with a consequent increase in bone fragility. The importance of trabecular and cortical bone microstructure to bone strength is well documented. Therefore evaluation of both microarchitecture and BMD may improve estimation of the risk of fracture. However, until recently the only way to assess bone microarchitecture was via histomorphometric analysis of iliac crest biopsies. Recently, noninvasive imaging methods, including high-resolution peripheral quantitative computed tomography (hr-pQCT) and high-resolution magnetic resonance imaging (hr-MRI), that allow in vivo 3D assessment of bone microstructure at peripheral skeletal sites have been developed. In addition, multi-detector QCT and flat-panel CT are being used to assess trabecular and cortical bone architecture. Recent studies indicate that in postmenopausal women, vertebral and non-vertebral fractures are associated with low volumetric bone density, architectural alterations of trabecular and cortical bone. These alterations are partially independent of aBMD assessed by DXA, suggesting that assessment of bone microarchitecture in vivo may provide improved sensitivity and/or specificity in identifying individuals at greatest risk for fracture. With a goal of outlining the potential clinical utility of these imaging modalities, this lecture will review the clinical studies with focus on three areas — use of bone architecture measurements to: 1) gain new insight to the patterns of age- and disease-related bone deterioration; 2) identify individuals at greatest risk for fracture; and 3) monitor treatment efficacy. The use of micro-finite element analysis based on hr-pQCT images will also be reviewed. The current data provide strong rationale for prospective studies to determine the utility of assessing microarchitecture for predicting the risk of osteoporotic fractures, as well as monitoring disease progression and the response to treatments. doi:10.1016/j.bone.2009.01.087
050 Vitamin D, falls and fractures — What's new? F.H. Anderson Healthy Ageing Group, University of Southampton, Southampton, United Kingdom Vitamin D deficiency and insufficiency are strongly associated with osteoporosis and fracture. Vitamin D also seems important to