Natalie Sims | University of Melbourne (original) (raw)

Papers by Natalie Sims

Research paper thumbnail of Dmp1Cre ‐ directed knockdown of parathyroid hormone–related protein (PTHrP) in murine decidua is associated with a life‐long increase in bone mass, width, and strength in male progeny

Journal of Bone and Mineral Research

Research paper thumbnail of Editorial Peer Reviewers as Shepherds, Rather Than Gatekeepers

Journal of Bone and Mineral Research

Research paper thumbnail of The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology

Experimental & Molecular Medicine

Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracr... more Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation thro...

Research paper thumbnail of Measuring Bone Volume at Multiple Densities by Micro-computed Tomography

Research paper thumbnail of Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes

eLife

Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we... more Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre:Socs3f/f mice. SOCS3 (suppressor of cytokine signalling 3) inhibits signalling by leptin, G-CSF, and IL-6 family cytokines (gp130). In Dmp1Cre:Socs3f/f bone, STAT3 phosphorylation was prolonged in response to gp130-signalling cytokines, but not G-CSF or leptin. Deletion of gp130 in Dmp1Cre:Socs3f/f mice suppressed STAT3 phosphorylation in osteocytes and osteoclastic resorption within cortical bone, leading to rescue of the corticalisation defect, and restoration of compromised bone strength. We conclude that cortical bone developmen...

Research paper thumbnail of The Cells of Bone and Their Interactions

Handbook of Experimental Pharmacology

Research paper thumbnail of Mobilizing Agents G-CSF, Cyclophosphamide or AMD3100 (Plerixafor) Have Distinct Effects on Osteoblasts, Hematopoietic Stem Cell Niches, and B-Lymphopoiesis

Blood

4005 The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide as adjuvant to G-CS... more 4005 The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide as adjuvant to G-CSF to mobilize hematopoietic stem cells (HSC) for autologous transplants in patients who failed prior mobilization with G-CSF alone. We and others have recently demonstrated that G-CSF-induced mobilization and the associated response of HSC niches and bone formation depend on bone marrow (BM) macrophages1–3. Moreover medullar B lymphopoiesis is dependent on bone-forming osteoblasts in vivo. We therefore compared the effects of these three mobilizing agents (6 day course of G-CSF, versus a single injection of cyclophosphamide, versus 6 day course of AMD3100) on endosteal osteoblasts, bone formation, BM macrophages, expression of HSC-supportive cytokines and B lymphopoiesis in the mouse. G-CSF administration significantly reduced the number of endosteal osteoblasts and niche-supporting macrophages. G-CSF also inhibited expression of chemokines and cytokines such as CXCL12, Kit-ligand, angio...

Research paper thumbnail of Cellular Processes by Which Osteoblasts and Osteocytes Control Bone Mineral Deposition and Maturation Revealed by Stage-Specific EphrinB2 Knockdown

Current Osteoporosis Reports

Research paper thumbnail of F1000Prime recommendation of Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate

F1000 - Post-publication peer review of the biomedical literature

Active cell proliferation and turnover in the growth plate is essential for embryonic and postnat... more Active cell proliferation and turnover in the growth plate is essential for embryonic and postnatal bone growth. We performed a lineage tracing of Wnt/β-catenin signaling responsive cells (Wntresponsive cells) using Axin2 CreERT2 ;Rosa26ZsGreen mice and found a novel cell population that resides in the outermost layer of the growth plate facing the Ranvier's groove (RG, the perichondrium adjacent to growth plate). These Wnt-responsive cells rapidly expanded and contributed to formation of the outer growth plate from the neonatal to the growing stage, but stopped expanding at the young adult stage when bone longitudinal growth ceases. In addition, a second Wnt-responsive sporadic cell population was localized within the resting zone of the central part of the growth plate during the postnatal growth phase. While it induced ectopic chondrogenesis in the RG, ablation of β-catenin in the Wnt-responsive cells strongly inhibited expansion of their descendants toward the growth plate. These findings indicate that the Wnt-*

Research paper thumbnail of F1000Prime recommendation of A network of trans-cortical capillaries as mainstay for blood circulation in long bones

F1000 - Post-publication peer review of the biomedical literature

Research paper thumbnail of Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease

The Journal of clinical investigation, 2018

Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that affli... more Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical tra...

Research paper thumbnail of Differing Effects of Parathyroid Hormone, Alendronate, and Odanacatib on Bone Formation and on the Mineralization Process in Intracortical and Endocortical Bone of Ovariectomized Rabbits

Calcified tissue international, Jan 17, 2018

Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as ... more Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as mineral crystals accrue and are modified; this continues until bone remodeling renews that site. Pharmacological agents for osteoporosis differ in their effects on bone remodeling, and we hypothesized that they may differently modify bone mineral accrual. We, therefore, assessed newly formed bone in mature ovariectomized rabbits treated with the anti-resorptive bisphosphonate alendronate (ALN-100µ g/kg/2×/week), the anabolic parathyroid hormone (PTH (1-34)-15µ g/kg/5×/week), or the experimental anti-resorptive odanacatib (ODN 7.5 µM/day), which suppresses bone resorption without suppressing bone formation. Treatments were administered for 10 months commencing 6 months after ovariectomy (OVX). Strength testing, histomorphometry, and synchrotron Fourier-transform infrared microspectroscopy were used to measure bone strength, bone formation, and mineral accrual, respectively, in newly forme...

Research paper thumbnail of Retinoic acid receptor γ activity in mesenchymal stem cells regulates endochondral bone, angiogenesis and B lymphopoiesis

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 24, 2018

Retinoic acid receptor (RAR) signaling regulates bone structure and hematopoiesis through intrins... more Retinoic acid receptor (RAR) signaling regulates bone structure and hematopoiesis through intrinsic and extrinsic mechanisms. This study aimed to establish how early in the osteoblast lineage loss of Rarg disrupts the bone marrow microenvironment. Bone structure was analyzed by microCT in Rarg mice and mice with Rarg conditional deletion in Osterix-Cre-targeted osteoblast progenitors or Prrx1-Cre-targeted mesenchymal stem cells. Rarg tibiae exhibited less trabecular and cortical bone and impaired longitudinal and radial growth. The trabecular bone and longitudinal, but not radial, growth defects were recapitulated in Prrx1:Rarg mice but not Osx1:Rarg mice. While both male and female Prrx1:Rarg mice had low trabecular bone mass, males exhibited increased numbers of trabecular osteoclasts and Prrx1:Rarg females had impaired mineral deposition. Both male and female Prrx1:Rarg growth plates were narrower than controls and their epiphyses contained hypertrophic chondrocyte islands. Flow ...

Research paper thumbnail of Parathyroid Hormone-Related Protein Negatively Regulates Tumor Cell Dormancy Genes in a PTHR1/Cyclic AMP-Independent Manner

Frontiers in endocrinology, 2018

Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metas... more Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metastases compared to primary tumors. Human MCF7 breast cancer cells "home" to the bones of immune deficient mice following intracardiac inoculation, but do not grow well and stain negatively for Ki67, thus serving as a model of breast cancer dormancy . We have previously shown that PTHrP overexpression in MCF7 cells overcomes this dormant phenotype, causing them to grow as osteolytic deposits, and that PTHrP-overexpressing MCF7 cells showed significantly lower expression of genes associated with dormancy compared to vector controls. Since early work showed a lack of cyclic AMP (cAMP) response to parathyroid hormone (PTH) in MCF7 cells, and cAMP is activated by PTH/PTHrP receptor (PTHR1) signaling, we hypothesized that the effects of PTHrP on dormancy in MCF7 cells occur through non-canonical (i.e., PTHR1/cAMP-independent) signaling. The data presented here demonstrate the lack of ...

Research paper thumbnail of Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 27, 2017

Research paper thumbnail of Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

JCI insight, Jan 2, 2017

Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles s... more Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages c...

Research paper thumbnail of Autocrine and paracrine regulation of the murine skeleton by osteocyte-derived parathyroid hormone-related protein

Journal of Bone and Mineral Research

This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Research paper thumbnail of High dose dietary vitamin D3 increases bone mass and strength in mice

Bone reports, 2017

Vitamin D plays a critical role in skeletal homeostasis. Vitamin D supplementation is used worldw... more Vitamin D plays a critical role in skeletal homeostasis. Vitamin D supplementation is used worldwide to maintain optimal bone health, but the most appropriate level of supplementation remains controversial. This study aimed to determine the effects of varying doses of dietary vitamin D3 on the mechanical properties and morphology of growing bone. Eight-week-old female mice were supplied with one of 3 diets, each containing a different dose of vitamin D3: 1000 IU/kg (control), 8000 IU/kg or 20,000 IU/kg. Mice had ad libitum access to the specialty diet for 4 weeks before they were culled and their tibiae collected for further analysis. The collected tibia underwent three-point bending and reference-point indentation from which their mechanical properties were determined, and cortical and trabecular morphology determined by micro computed tomography. Dietary supplementation with 20,000 IU/kg vitamin D3 resulted in greater ductility (~ 200%) and toughness (~ 150%) compared to the 1000 ...

Research paper thumbnail of Senescent Osteocytes: Do They Cause Damage and Can They Be Targeted to Preserve the Skeleton?

Journal of Bone and Mineral Research, 2016

Research paper thumbnail of Bone: Does anti-sclerostin therapy promote inflammation in rheumatoid arthritis?

Nature Reviews Endocrinology, 2016

Research paper thumbnail of Dmp1Cre ‐ directed knockdown of parathyroid hormone–related protein (PTHrP) in murine decidua is associated with a life‐long increase in bone mass, width, and strength in male progeny

Journal of Bone and Mineral Research

Research paper thumbnail of Editorial Peer Reviewers as Shepherds, Rather Than Gatekeepers

Journal of Bone and Mineral Research

Research paper thumbnail of The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology

Experimental & Molecular Medicine

Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracr... more Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation thro...

Research paper thumbnail of Measuring Bone Volume at Multiple Densities by Micro-computed Tomography

Research paper thumbnail of Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes

eLife

Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we... more Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre:Socs3f/f mice. SOCS3 (suppressor of cytokine signalling 3) inhibits signalling by leptin, G-CSF, and IL-6 family cytokines (gp130). In Dmp1Cre:Socs3f/f bone, STAT3 phosphorylation was prolonged in response to gp130-signalling cytokines, but not G-CSF or leptin. Deletion of gp130 in Dmp1Cre:Socs3f/f mice suppressed STAT3 phosphorylation in osteocytes and osteoclastic resorption within cortical bone, leading to rescue of the corticalisation defect, and restoration of compromised bone strength. We conclude that cortical bone developmen...

Research paper thumbnail of The Cells of Bone and Their Interactions

Handbook of Experimental Pharmacology

Research paper thumbnail of Mobilizing Agents G-CSF, Cyclophosphamide or AMD3100 (Plerixafor) Have Distinct Effects on Osteoblasts, Hematopoietic Stem Cell Niches, and B-Lymphopoiesis

Blood

4005 The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide as adjuvant to G-CS... more 4005 The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide as adjuvant to G-CSF to mobilize hematopoietic stem cells (HSC) for autologous transplants in patients who failed prior mobilization with G-CSF alone. We and others have recently demonstrated that G-CSF-induced mobilization and the associated response of HSC niches and bone formation depend on bone marrow (BM) macrophages1–3. Moreover medullar B lymphopoiesis is dependent on bone-forming osteoblasts in vivo. We therefore compared the effects of these three mobilizing agents (6 day course of G-CSF, versus a single injection of cyclophosphamide, versus 6 day course of AMD3100) on endosteal osteoblasts, bone formation, BM macrophages, expression of HSC-supportive cytokines and B lymphopoiesis in the mouse. G-CSF administration significantly reduced the number of endosteal osteoblasts and niche-supporting macrophages. G-CSF also inhibited expression of chemokines and cytokines such as CXCL12, Kit-ligand, angio...

Research paper thumbnail of Cellular Processes by Which Osteoblasts and Osteocytes Control Bone Mineral Deposition and Maturation Revealed by Stage-Specific EphrinB2 Knockdown

Current Osteoporosis Reports

Research paper thumbnail of F1000Prime recommendation of Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate

F1000 - Post-publication peer review of the biomedical literature

Active cell proliferation and turnover in the growth plate is essential for embryonic and postnat... more Active cell proliferation and turnover in the growth plate is essential for embryonic and postnatal bone growth. We performed a lineage tracing of Wnt/β-catenin signaling responsive cells (Wntresponsive cells) using Axin2 CreERT2 ;Rosa26ZsGreen mice and found a novel cell population that resides in the outermost layer of the growth plate facing the Ranvier's groove (RG, the perichondrium adjacent to growth plate). These Wnt-responsive cells rapidly expanded and contributed to formation of the outer growth plate from the neonatal to the growing stage, but stopped expanding at the young adult stage when bone longitudinal growth ceases. In addition, a second Wnt-responsive sporadic cell population was localized within the resting zone of the central part of the growth plate during the postnatal growth phase. While it induced ectopic chondrogenesis in the RG, ablation of β-catenin in the Wnt-responsive cells strongly inhibited expansion of their descendants toward the growth plate. These findings indicate that the Wnt-*

Research paper thumbnail of F1000Prime recommendation of A network of trans-cortical capillaries as mainstay for blood circulation in long bones

F1000 - Post-publication peer review of the biomedical literature

Research paper thumbnail of Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease

The Journal of clinical investigation, 2018

Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that affli... more Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical tra...

Research paper thumbnail of Differing Effects of Parathyroid Hormone, Alendronate, and Odanacatib on Bone Formation and on the Mineralization Process in Intracortical and Endocortical Bone of Ovariectomized Rabbits

Calcified tissue international, Jan 17, 2018

Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as ... more Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as mineral crystals accrue and are modified; this continues until bone remodeling renews that site. Pharmacological agents for osteoporosis differ in their effects on bone remodeling, and we hypothesized that they may differently modify bone mineral accrual. We, therefore, assessed newly formed bone in mature ovariectomized rabbits treated with the anti-resorptive bisphosphonate alendronate (ALN-100µ g/kg/2×/week), the anabolic parathyroid hormone (PTH (1-34)-15µ g/kg/5×/week), or the experimental anti-resorptive odanacatib (ODN 7.5 µM/day), which suppresses bone resorption without suppressing bone formation. Treatments were administered for 10 months commencing 6 months after ovariectomy (OVX). Strength testing, histomorphometry, and synchrotron Fourier-transform infrared microspectroscopy were used to measure bone strength, bone formation, and mineral accrual, respectively, in newly forme...

Research paper thumbnail of Retinoic acid receptor γ activity in mesenchymal stem cells regulates endochondral bone, angiogenesis and B lymphopoiesis

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 24, 2018

Retinoic acid receptor (RAR) signaling regulates bone structure and hematopoiesis through intrins... more Retinoic acid receptor (RAR) signaling regulates bone structure and hematopoiesis through intrinsic and extrinsic mechanisms. This study aimed to establish how early in the osteoblast lineage loss of Rarg disrupts the bone marrow microenvironment. Bone structure was analyzed by microCT in Rarg mice and mice with Rarg conditional deletion in Osterix-Cre-targeted osteoblast progenitors or Prrx1-Cre-targeted mesenchymal stem cells. Rarg tibiae exhibited less trabecular and cortical bone and impaired longitudinal and radial growth. The trabecular bone and longitudinal, but not radial, growth defects were recapitulated in Prrx1:Rarg mice but not Osx1:Rarg mice. While both male and female Prrx1:Rarg mice had low trabecular bone mass, males exhibited increased numbers of trabecular osteoclasts and Prrx1:Rarg females had impaired mineral deposition. Both male and female Prrx1:Rarg growth plates were narrower than controls and their epiphyses contained hypertrophic chondrocyte islands. Flow ...

Research paper thumbnail of Parathyroid Hormone-Related Protein Negatively Regulates Tumor Cell Dormancy Genes in a PTHR1/Cyclic AMP-Independent Manner

Frontiers in endocrinology, 2018

Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metas... more Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metastases compared to primary tumors. Human MCF7 breast cancer cells "home" to the bones of immune deficient mice following intracardiac inoculation, but do not grow well and stain negatively for Ki67, thus serving as a model of breast cancer dormancy . We have previously shown that PTHrP overexpression in MCF7 cells overcomes this dormant phenotype, causing them to grow as osteolytic deposits, and that PTHrP-overexpressing MCF7 cells showed significantly lower expression of genes associated with dormancy compared to vector controls. Since early work showed a lack of cyclic AMP (cAMP) response to parathyroid hormone (PTH) in MCF7 cells, and cAMP is activated by PTH/PTHrP receptor (PTHR1) signaling, we hypothesized that the effects of PTHrP on dormancy in MCF7 cells occur through non-canonical (i.e., PTHR1/cAMP-independent) signaling. The data presented here demonstrate the lack of ...

Research paper thumbnail of Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 27, 2017

Research paper thumbnail of Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

JCI insight, Jan 2, 2017

Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles s... more Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages c...

Research paper thumbnail of Autocrine and paracrine regulation of the murine skeleton by osteocyte-derived parathyroid hormone-related protein

Journal of Bone and Mineral Research

This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Research paper thumbnail of High dose dietary vitamin D3 increases bone mass and strength in mice

Bone reports, 2017

Vitamin D plays a critical role in skeletal homeostasis. Vitamin D supplementation is used worldw... more Vitamin D plays a critical role in skeletal homeostasis. Vitamin D supplementation is used worldwide to maintain optimal bone health, but the most appropriate level of supplementation remains controversial. This study aimed to determine the effects of varying doses of dietary vitamin D3 on the mechanical properties and morphology of growing bone. Eight-week-old female mice were supplied with one of 3 diets, each containing a different dose of vitamin D3: 1000 IU/kg (control), 8000 IU/kg or 20,000 IU/kg. Mice had ad libitum access to the specialty diet for 4 weeks before they were culled and their tibiae collected for further analysis. The collected tibia underwent three-point bending and reference-point indentation from which their mechanical properties were determined, and cortical and trabecular morphology determined by micro computed tomography. Dietary supplementation with 20,000 IU/kg vitamin D3 resulted in greater ductility (~ 200%) and toughness (~ 150%) compared to the 1000 ...

Research paper thumbnail of Senescent Osteocytes: Do They Cause Damage and Can They Be Targeted to Preserve the Skeleton?

Journal of Bone and Mineral Research, 2016

Research paper thumbnail of Bone: Does anti-sclerostin therapy promote inflammation in rheumatoid arthritis?

Nature Reviews Endocrinology, 2016