Better understanding of hemostasis will be possible by the identification of new lineage-specific... more Better understanding of hemostasis will be possible by the identification of new lineage-specific stimuli that regulate platelet formation. We describe a novel functional megakaryocyte receptor that belongs to a family of ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype responsible for synaptic neurotransmission in the central nervous system (CNS). Northern blotting and reverse-transcriptase polymerase chain reaction (RT-PCR) studies identified expression of NMDAR1 and NMDAR2D type subunit mRNA in rat marrow, human megakaryocytes, and MEG-01 clonal megakaryoblastic cells. Immunohistochemistry and in vivo autoradiographic binding of the NMDA receptor-specific antagonist MK-801 confirmed that megakaryocytes expressed open channel-forming NMDA receptors in vivo. Western blots indicated that megakaryocyte NMDAR1 was either unglycosylated or only glycosylated to low levels, and of identical size to CNS-type NMDAR1 after deglycosylation with endoglycosidase F/pept...
The inflammatory response is a process which forms a defence against the effects of trauma or inv... more The inflammatory response is a process which forms a defence against the effects of trauma or invasion by foreign organisms or substances. Inflammation is mediated by local and systemic changes in expression of its activators and inhibitors. Many of these regulators of inflammation are also the controllers of normal cellular activity, so the effects of inflammation are due to changes in the amounts, ratios and timings of their expression, rather than de novo expression of specific mediators of inflammation. The effects of inflammation on bone growth are two-fold. Firstly, systemic inflammatory effects have consequences on hormone, mineral and nutrient metabolism which affect bone growth. Secondly, cytokine mediators of inflammation cause local changes in cell regulation to influence both endochondral processes in the growth plate, and modelling and remodelling activity associated with appositional growth. The complexity of the osteotropic influences responsible for maintaining norma...
Abstracts from the 31 International Sun Valley Hard Tissue Workshops from the 31 International Su... more Abstracts from the 31 International Sun Valley Hard Tissue Workshops from the 31 International Sun Valley Hard Tissue Workshop 6-10 August 2001, Sun Valley, Idaho, USA Program Chairmen D.B. Burr and W.S.S. Jee OR-1 OSTEOPOROSIS IN WOMEN R.R. Recker Creighton University, Omaha, NE [email protected] The Sun Valley Workshop this year opens with a session on osteoporosis in women, to be followed by a session on osteoporosis in men. The sessions will characterize the "state-of-the-art" in both genders with attention paid to the differences between them and the insights those differences may give in understanding skeletal biology and biomechanics. The first session will be given by Dr. Robert Marcus and will give an overview of current questions in osteoporosis. He will present his view of the status of the questions, and in the process give background that introduces the topics of subsequent speakers. The subsequent speakers will be Drs. Cummings, Burr, Keaveny, Martin and ...
Bone strength and therefore its resistance to fracture are strongly correlated with the mass and ... more Bone strength and therefore its resistance to fracture are strongly correlated with the mass and orientation of the load-bearing extracellular matrix. The matrix is in turn the result of the orchestrated activity of osteoblasts and osteoclasts that form and model/remodel the tissue. Changes in bone mass and architecture are therefore linked directly to the regulated activity of those cells, and therefore the endocrine, paracrine and autocrine influences on them. An ability to influence intercellular communication would provide the basis for novel therapeutic strategies for bone diseases, but conventional approaches to the discovery of novel targets, and the search for and development of compounds capable of influencing them can be protracted. One way in which this process can be shortened is by the identification of a signalling pathway in bone that is known in another tissue, in which case, agents already developed for that tissue could have utility in bone. Such approaches have on...
Both ulnas of skeletally mature roosters (Gallus domesticus) were deprived of functional load bea... more Both ulnas of skeletally mature roosters (Gallus domesticus) were deprived of functional load bearing by proximal and distal submetaphyseal osteotomies. Twenty-four hours later the animals were injected with 1.5 mCi of 3H-uridine and the ulna on one side was subjected to a single period of a cyclical load engendering physiological strain levels at 1 Hz for 6 min. Twenty-four hours after loading the animals were killed. Autoradiographic examination of comparable regions of cortex in sections from the bone's midshafts showed that in the loaded bones, 72 +/- 2.7% of osteocytes were labeled compared with 12 +/- 3.5% in the corresponding areas of their contralateral nonloaded pair (P less than 0.001). The number of grains per labeled osteocyte was also higher in the loaded side (6 +/- 0.5 compared with 4 +/- 0.5, P less than 0.01). There was no obvious correlation between the longitudinal strain distribution during artificial loading and the distribution of labeled osteocytes through...
Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,00... more Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. Homozygous missense NBAS variants cause SOPH syndrome (sh...
Journal of applied physiology (Bethesda, Md. : 1985), 1996
The results of simple biomechanical unloading in models of acute-disuse osteoporosis are influenc... more The results of simple biomechanical unloading in models of acute-disuse osteoporosis are influenced by systemic and regional effects of the method used to generate the bone loss. A model in which strain-gauge measurements confirmed that the os calcis was unloaded in healthy ewes during ambulation was assessed by histomorphometry. Twelve nonovariectomized adult female Welsh mountain sheep were submitted to hock joint immobilization by an external fixation procedure from the tibia to the metatarsus for a period of 12 wk. Histomorphometric analysis showed that this model was able to produce pure local bone loss, as transiliac bone biopsies failed to reveal any difference between the initial and final results. Immobilized and nonimmobilized calcanei were both removed postmortem. After the 12 wk of the study, osteoclastic activity was increased in accordance with the usual disuse process. An unexpected increase of osteoblastic activity was also observed, possibly related to recovery afte...
Journal of musculoskeletal & neuronal interactions
The concept of the mechanostat was not new in 1983, when Harold Frost coined the term to describe... more The concept of the mechanostat was not new in 1983, when Harold Frost coined the term to describe a mechanism by which bone responded to habitual exercise and changes in loading with structurally appropriate alterations in bone architecture. However, the word "mechanostat" has a meaning that is immediately apparent, and its adoption has led to a much wider appreciation of the process of functional adaptation by other scientists than those whose primary research focus is in the biology of adaptation. One problem exists though: it is widely thought that in a single individual, there is a setting for the mechanostat, just as a single thermostat might set the temperature for a whole house, and this is reflected in the idea that bones throughout the skeleton require a specific strain magnitude for maintenance. Increases in loading above that threshold are expected to induce bone formation and a stiffer structure that then experiences again the habitual strain magnitude. Reducti...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1999
Recent identification in bone of transporters, receptors, and components of synaptic signaling su... more Recent identification in bone of transporters, receptors, and components of synaptic signaling suggests a role for glutamate in the skeleton. We investigated effects of glutamate and its antagonist MK801 on osteoclasts in vitro. Glutamate applied to patch clamped osteoclasts induced significant increases in whole-cell membrane currents (P<0.01) in the presence of the coagonist glycine. Agonist-elicited currents were significantly decreased after application of MK801 (100 microM, P<0.01), but MK801 had no effect on actin ring formation necessary for osteoclast polarization, attachment, and resorption. In cocultures of bone marrow cells and osteoblasts in which osteoclasts develop, MK801 inhibited osteoclast differentiation and reduced resorption of pits in dentine (3 to 100 microM; P<0.001). MK801 added early in the culture (for as little as 2-4 days) was as effective as addition for the entire culture period. Addition of MK801 for any time after day 7 of culture was ineffec...
NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine,... more NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine, as in human, patients receiving these drugs for treatment of pain in osteoarthritis and other acute and chronic painful conditions. To determine the potential effects of the new NSAID meloxicam on cartilage integrity, the effects of this drug on proteoglycan biosynthesis in vitro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoarthritis. In vitro cartilage proteoglycan synthesis from a radiosulphate precursor was unaffected by 0.5-10.0 micromol/L meloxicam but was significantly inhibited by 50 micromol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage explants in organ culture. This is in accord with previous observations in human or porcine articular cartilage under the same culture conditions. Studies were performed in vivo to establish the effects of the NSAIDs on joi...
Objectives. Synovial fluid (SF) of normal joints contains high hyaluronan (HA) concentrations. Ho... more Objectives. Synovial fluid (SF) of normal joints contains high hyaluronan (HA) concentrations. However, the mechanism by which these are controlled and how they are influenced by articulation and loading are not established. In this study, we have examined whether immobilization influences SF HA concentration and whether this is associated with alterations in the synovial lining. Methods. Hock joints of five adult sheep were immobilized by external fixation. Twelve weeks later, SF and synovium samples were collected. The HA concentration in SF was assayed using an ELISA-based method. Non-specific esterase (NSE) and uridine diphosphoglucose dehydrogenase (UDPGD) activities were assessed in cryostat sections of snap-chilled synovial samples using cytochemical techniques, and UDPGD activity per cell was measured in synovial lining cells by scanning and integrating microdensitometry. Results. We found that the SF HA concentration was decreased from 1.65 ± 0.25 mg/ml in control joints to 0.68 ± 0.16 mg/ml in immobilized joints. Synovial intimal cell UDPGD activity decreased from 18.0 ± 2.7 U/cell in control joints to 12.2 ± 1.5 after immobilization. There was also a decrease in UDPGD-positive intimal cell numbers. Intimal surfaces in controls contained numerous NSE-positive cells, which were rarely observed in intima from immobilized joints. Conclusions. These results suggest that immobilization decreases SF HA levels and that this is associated with reduced intimal cell UDPGD activity (essential for HA formation). Immobilization also decreased the prevalence of (NSE-positive) intimal macrophages. These findings suggest that mechanosensitive homeostatic mechanisms exist within the synovial intima.
The ability of trabeculae to reform following localized ablation may provide further insight into... more The ability of trabeculae to reform following localized ablation may provide further insight into the sequence of events in cancellous regeneration. Histological features of cancellous repair were examined in the iliac crest of aged female sheep at intervals after removal of a 1-cm diameter biopsy. Comparison was made with normal intramembranous trabecular formation in the foetal lamb. The first immature trabeculae to form in the defects within 3 weeks were exclusively intramembranous, not endochondral, and the systematic process was indistinguishable from that in the intact growing foetal lamb. In both the young and old skeleton, two features were prominent. First, the damaged endosteum of the sheep functioned like the intact periosteum of the lamb to produce orderly migrating arrays of discrete coarse collagenous fibres, 5-25 microns thick, which penetrated the surrounding soft tissues to form a polarised preliminary framework. Without this structure, primary trabecular development did not take place. Throughout subsequent bone apposition the preliminary framework, which bonded hard to soft tissues and new bone to old, remained largely unmineralised. Second, intratrabecular resorption channels divided the established, thickened primary bars into networks of mature secondary trabeculae. It is concluded that the two features are central and universal to trabecular proliferation and may provide a morphological basis for future trabecular restitution of the depleted elderly skeleton.
Novel Approaches to Treatment of Osteoporosis, 1998
In the search for therapies to increase bone mass, it is not surprising that much attention has f... more In the search for therapies to increase bone mass, it is not surprising that much attention has focused on studies of the effects of mechanical loading on the skeleton. Historical comments on the stronger skeletons of individuals with active lifestyles are attributed to Galileo, but serious studies of the relationships between bone mass and loading were not made until the late 1800s, when Culmann, von Meyer, Roux and Wolff initiated what has now become the idea of functional adaptation in the skeleton. Since then, studies have been predominantly phenomenological, cataloguing the changes in bone mass in response to exercise, disuse and applied loading. That is not to say that the data have not had important applications. For example, studies which have determined the numbers, rates and magnitudes of loads which influence bone mass have been useful in order to develop appropriate exercise regimens for improvement of bone mass. In addition it has become clear from clinical studies that exercise which fails to increase bone mass may still reduce the risk of fractures in osteoporotic individuals. This is because the increased muscle power and coordination which accompany increased fitness reduce the risk of falling, and therefore incidence of fracture.
The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calva... more The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calvarial cells, which form mineralized bonelike nodules, both LTBP and the TGF-beta 1 precursor localized to large fibrillar structures in the extracellular matrix. The appearance of these fibrillar structures preceded the appearance of type I collagen fibers. Plasmin treatment abolished the fibrillar staining pattern for LTBP and released a complex containing both LTBP and TGF-beta. Antibodies and antisense oligonucleotides against LTBP inhibited the formation of mineralized bonelike nodules in long-term fetal rat calvarial cultures. Immunohistochemistry of fetal and adult rat bone confirmed a fibrillar staining pattern for LTBP in vivo. These findings, together with the known homology of LTBP to the fibrillin family of proteins, suggest a novel function for LTBP, in addition to its role in matrix storage of latent TGF-beta, as a structural matrix protein that may play a role in bone format...
Better understanding of hemostasis will be possible by the identification of new lineage-specific... more Better understanding of hemostasis will be possible by the identification of new lineage-specific stimuli that regulate platelet formation. We describe a novel functional megakaryocyte receptor that belongs to a family of ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype responsible for synaptic neurotransmission in the central nervous system (CNS). Northern blotting and reverse-transcriptase polymerase chain reaction (RT-PCR) studies identified expression of NMDAR1 and NMDAR2D type subunit mRNA in rat marrow, human megakaryocytes, and MEG-01 clonal megakaryoblastic cells. Immunohistochemistry and in vivo autoradiographic binding of the NMDA receptor-specific antagonist MK-801 confirmed that megakaryocytes expressed open channel-forming NMDA receptors in vivo. Western blots indicated that megakaryocyte NMDAR1 was either unglycosylated or only glycosylated to low levels, and of identical size to CNS-type NMDAR1 after deglycosylation with endoglycosidase F/pept...
The inflammatory response is a process which forms a defence against the effects of trauma or inv... more The inflammatory response is a process which forms a defence against the effects of trauma or invasion by foreign organisms or substances. Inflammation is mediated by local and systemic changes in expression of its activators and inhibitors. Many of these regulators of inflammation are also the controllers of normal cellular activity, so the effects of inflammation are due to changes in the amounts, ratios and timings of their expression, rather than de novo expression of specific mediators of inflammation. The effects of inflammation on bone growth are two-fold. Firstly, systemic inflammatory effects have consequences on hormone, mineral and nutrient metabolism which affect bone growth. Secondly, cytokine mediators of inflammation cause local changes in cell regulation to influence both endochondral processes in the growth plate, and modelling and remodelling activity associated with appositional growth. The complexity of the osteotropic influences responsible for maintaining norma...
Abstracts from the 31 International Sun Valley Hard Tissue Workshops from the 31 International Su... more Abstracts from the 31 International Sun Valley Hard Tissue Workshops from the 31 International Sun Valley Hard Tissue Workshop 6-10 August 2001, Sun Valley, Idaho, USA Program Chairmen D.B. Burr and W.S.S. Jee OR-1 OSTEOPOROSIS IN WOMEN R.R. Recker Creighton University, Omaha, NE [email protected] The Sun Valley Workshop this year opens with a session on osteoporosis in women, to be followed by a session on osteoporosis in men. The sessions will characterize the "state-of-the-art" in both genders with attention paid to the differences between them and the insights those differences may give in understanding skeletal biology and biomechanics. The first session will be given by Dr. Robert Marcus and will give an overview of current questions in osteoporosis. He will present his view of the status of the questions, and in the process give background that introduces the topics of subsequent speakers. The subsequent speakers will be Drs. Cummings, Burr, Keaveny, Martin and ...
Bone strength and therefore its resistance to fracture are strongly correlated with the mass and ... more Bone strength and therefore its resistance to fracture are strongly correlated with the mass and orientation of the load-bearing extracellular matrix. The matrix is in turn the result of the orchestrated activity of osteoblasts and osteoclasts that form and model/remodel the tissue. Changes in bone mass and architecture are therefore linked directly to the regulated activity of those cells, and therefore the endocrine, paracrine and autocrine influences on them. An ability to influence intercellular communication would provide the basis for novel therapeutic strategies for bone diseases, but conventional approaches to the discovery of novel targets, and the search for and development of compounds capable of influencing them can be protracted. One way in which this process can be shortened is by the identification of a signalling pathway in bone that is known in another tissue, in which case, agents already developed for that tissue could have utility in bone. Such approaches have on...
Both ulnas of skeletally mature roosters (Gallus domesticus) were deprived of functional load bea... more Both ulnas of skeletally mature roosters (Gallus domesticus) were deprived of functional load bearing by proximal and distal submetaphyseal osteotomies. Twenty-four hours later the animals were injected with 1.5 mCi of 3H-uridine and the ulna on one side was subjected to a single period of a cyclical load engendering physiological strain levels at 1 Hz for 6 min. Twenty-four hours after loading the animals were killed. Autoradiographic examination of comparable regions of cortex in sections from the bone's midshafts showed that in the loaded bones, 72 +/- 2.7% of osteocytes were labeled compared with 12 +/- 3.5% in the corresponding areas of their contralateral nonloaded pair (P less than 0.001). The number of grains per labeled osteocyte was also higher in the loaded side (6 +/- 0.5 compared with 4 +/- 0.5, P less than 0.01). There was no obvious correlation between the longitudinal strain distribution during artificial loading and the distribution of labeled osteocytes through...
Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,00... more Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. Homozygous missense NBAS variants cause SOPH syndrome (sh...
Journal of applied physiology (Bethesda, Md. : 1985), 1996
The results of simple biomechanical unloading in models of acute-disuse osteoporosis are influenc... more The results of simple biomechanical unloading in models of acute-disuse osteoporosis are influenced by systemic and regional effects of the method used to generate the bone loss. A model in which strain-gauge measurements confirmed that the os calcis was unloaded in healthy ewes during ambulation was assessed by histomorphometry. Twelve nonovariectomized adult female Welsh mountain sheep were submitted to hock joint immobilization by an external fixation procedure from the tibia to the metatarsus for a period of 12 wk. Histomorphometric analysis showed that this model was able to produce pure local bone loss, as transiliac bone biopsies failed to reveal any difference between the initial and final results. Immobilized and nonimmobilized calcanei were both removed postmortem. After the 12 wk of the study, osteoclastic activity was increased in accordance with the usual disuse process. An unexpected increase of osteoblastic activity was also observed, possibly related to recovery afte...
Journal of musculoskeletal & neuronal interactions
The concept of the mechanostat was not new in 1983, when Harold Frost coined the term to describe... more The concept of the mechanostat was not new in 1983, when Harold Frost coined the term to describe a mechanism by which bone responded to habitual exercise and changes in loading with structurally appropriate alterations in bone architecture. However, the word "mechanostat" has a meaning that is immediately apparent, and its adoption has led to a much wider appreciation of the process of functional adaptation by other scientists than those whose primary research focus is in the biology of adaptation. One problem exists though: it is widely thought that in a single individual, there is a setting for the mechanostat, just as a single thermostat might set the temperature for a whole house, and this is reflected in the idea that bones throughout the skeleton require a specific strain magnitude for maintenance. Increases in loading above that threshold are expected to induce bone formation and a stiffer structure that then experiences again the habitual strain magnitude. Reducti...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1999
Recent identification in bone of transporters, receptors, and components of synaptic signaling su... more Recent identification in bone of transporters, receptors, and components of synaptic signaling suggests a role for glutamate in the skeleton. We investigated effects of glutamate and its antagonist MK801 on osteoclasts in vitro. Glutamate applied to patch clamped osteoclasts induced significant increases in whole-cell membrane currents (P<0.01) in the presence of the coagonist glycine. Agonist-elicited currents were significantly decreased after application of MK801 (100 microM, P<0.01), but MK801 had no effect on actin ring formation necessary for osteoclast polarization, attachment, and resorption. In cocultures of bone marrow cells and osteoblasts in which osteoclasts develop, MK801 inhibited osteoclast differentiation and reduced resorption of pits in dentine (3 to 100 microM; P<0.001). MK801 added early in the culture (for as little as 2-4 days) was as effective as addition for the entire culture period. Addition of MK801 for any time after day 7 of culture was ineffec...
NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine,... more NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine, as in human, patients receiving these drugs for treatment of pain in osteoarthritis and other acute and chronic painful conditions. To determine the potential effects of the new NSAID meloxicam on cartilage integrity, the effects of this drug on proteoglycan biosynthesis in vitro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoarthritis. In vitro cartilage proteoglycan synthesis from a radiosulphate precursor was unaffected by 0.5-10.0 micromol/L meloxicam but was significantly inhibited by 50 micromol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage explants in organ culture. This is in accord with previous observations in human or porcine articular cartilage under the same culture conditions. Studies were performed in vivo to establish the effects of the NSAIDs on joi...
Objectives. Synovial fluid (SF) of normal joints contains high hyaluronan (HA) concentrations. Ho... more Objectives. Synovial fluid (SF) of normal joints contains high hyaluronan (HA) concentrations. However, the mechanism by which these are controlled and how they are influenced by articulation and loading are not established. In this study, we have examined whether immobilization influences SF HA concentration and whether this is associated with alterations in the synovial lining. Methods. Hock joints of five adult sheep were immobilized by external fixation. Twelve weeks later, SF and synovium samples were collected. The HA concentration in SF was assayed using an ELISA-based method. Non-specific esterase (NSE) and uridine diphosphoglucose dehydrogenase (UDPGD) activities were assessed in cryostat sections of snap-chilled synovial samples using cytochemical techniques, and UDPGD activity per cell was measured in synovial lining cells by scanning and integrating microdensitometry. Results. We found that the SF HA concentration was decreased from 1.65 ± 0.25 mg/ml in control joints to 0.68 ± 0.16 mg/ml in immobilized joints. Synovial intimal cell UDPGD activity decreased from 18.0 ± 2.7 U/cell in control joints to 12.2 ± 1.5 after immobilization. There was also a decrease in UDPGD-positive intimal cell numbers. Intimal surfaces in controls contained numerous NSE-positive cells, which were rarely observed in intima from immobilized joints. Conclusions. These results suggest that immobilization decreases SF HA levels and that this is associated with reduced intimal cell UDPGD activity (essential for HA formation). Immobilization also decreased the prevalence of (NSE-positive) intimal macrophages. These findings suggest that mechanosensitive homeostatic mechanisms exist within the synovial intima.
The ability of trabeculae to reform following localized ablation may provide further insight into... more The ability of trabeculae to reform following localized ablation may provide further insight into the sequence of events in cancellous regeneration. Histological features of cancellous repair were examined in the iliac crest of aged female sheep at intervals after removal of a 1-cm diameter biopsy. Comparison was made with normal intramembranous trabecular formation in the foetal lamb. The first immature trabeculae to form in the defects within 3 weeks were exclusively intramembranous, not endochondral, and the systematic process was indistinguishable from that in the intact growing foetal lamb. In both the young and old skeleton, two features were prominent. First, the damaged endosteum of the sheep functioned like the intact periosteum of the lamb to produce orderly migrating arrays of discrete coarse collagenous fibres, 5-25 microns thick, which penetrated the surrounding soft tissues to form a polarised preliminary framework. Without this structure, primary trabecular development did not take place. Throughout subsequent bone apposition the preliminary framework, which bonded hard to soft tissues and new bone to old, remained largely unmineralised. Second, intratrabecular resorption channels divided the established, thickened primary bars into networks of mature secondary trabeculae. It is concluded that the two features are central and universal to trabecular proliferation and may provide a morphological basis for future trabecular restitution of the depleted elderly skeleton.
Novel Approaches to Treatment of Osteoporosis, 1998
In the search for therapies to increase bone mass, it is not surprising that much attention has f... more In the search for therapies to increase bone mass, it is not surprising that much attention has focused on studies of the effects of mechanical loading on the skeleton. Historical comments on the stronger skeletons of individuals with active lifestyles are attributed to Galileo, but serious studies of the relationships between bone mass and loading were not made until the late 1800s, when Culmann, von Meyer, Roux and Wolff initiated what has now become the idea of functional adaptation in the skeleton. Since then, studies have been predominantly phenomenological, cataloguing the changes in bone mass in response to exercise, disuse and applied loading. That is not to say that the data have not had important applications. For example, studies which have determined the numbers, rates and magnitudes of loads which influence bone mass have been useful in order to develop appropriate exercise regimens for improvement of bone mass. In addition it has become clear from clinical studies that exercise which fails to increase bone mass may still reduce the risk of fractures in osteoporotic individuals. This is because the increased muscle power and coordination which accompany increased fitness reduce the risk of falling, and therefore incidence of fracture.
The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calva... more The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calvarial cells, which form mineralized bonelike nodules, both LTBP and the TGF-beta 1 precursor localized to large fibrillar structures in the extracellular matrix. The appearance of these fibrillar structures preceded the appearance of type I collagen fibers. Plasmin treatment abolished the fibrillar staining pattern for LTBP and released a complex containing both LTBP and TGF-beta. Antibodies and antisense oligonucleotides against LTBP inhibited the formation of mineralized bonelike nodules in long-term fetal rat calvarial cultures. Immunohistochemistry of fetal and adult rat bone confirmed a fibrillar staining pattern for LTBP in vivo. These findings, together with the known homology of LTBP to the fibrillin family of proteins, suggest a novel function for LTBP, in addition to its role in matrix storage of latent TGF-beta, as a structural matrix protein that may play a role in bone format...
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Papers by T. Skerry