Julia Charles - Academia.edu (original) (raw)
Papers by Julia Charles
Frontiers in Pharmacology, Nov 22, 2023
Proceedings of the National Academy of Sciences of the United States of America, Nov 7, 2016
Journal of the Endocrine Society, May 1, 2021
bioRxiv (Cold Spring Harbor Laboratory), Jan 14, 2020
Elsevier eBooks, 2020
Abstract Bone remodeling occurs through the interactions of two major cell lineages, osteoblasts,... more Abstract Bone remodeling occurs through the interactions of two major cell lineages, osteoblasts, which mediates bone formation, and osteoclasts, which mediate bone resorption. This review provides a through introduction to the myeloid precursors of osteoclasts, the signals that induce their differentiation, the signaling pathways and transcription factors that control their differentiation, fusion and resorptive actions.
Jcr-journal of Clinical Rheumatology, 2011
... Resolution of Recurrent Fusarium Arthritis After Prolonged Antifungal Therapy. Charles, Julia... more ... Resolution of Recurrent Fusarium Arthritis After Prolonged Antifungal Therapy. Charles, Julia F. MD, PhD*; Eberle, Carey MD; Daikh, David I. MD, PhD*; Rooney, Terence MD*. Article Outline. Collapse Box ... Cited Here... 4. Cooke NS, Feighery C, Armstrong DK, et al. ...
HAND
Background: The purpose of this study was to assess the impact of implementation of an outpatient... more Background: The purpose of this study was to assess the impact of implementation of an outpatient fracture liaison service (FLS) on completion rates of dual-energy x-ray absorptiometry (DXA) and screening labs including 25-OH vitamin D and parathyroid hormone (PTH) in patients with upper extremity (UE) fragility fractures. Methods: At our institution, 367 patients were treated in 2014-2015 for UE fragility fractures of the distal radius and proximal humerus before implementation of our outpatient FLS and 395 patients in 2017-2018 after implementation. Retrospective chart review was conducted to identify completed DXA scans within 2 years of fracture treatment and completed 25-OH vitamin D and PTH labs within 1 year of fracture treatment. Results: There were no statistical differences in the demographics of patients treated for distal radial and proximal humeral fragility fractures during the 2014-2015 and 2017-2018 time periods. Implementation of the FLS resulted in a 9.9% increase ...
mSystems
Aging-associated microbial alteration is hypothesized to play an important role in host health an... more Aging-associated microbial alteration is hypothesized to play an important role in host health and longevity. However, investigations regarding specific gut microbes or microbial functional alterations associated with aging have had inconsistent results.
Laboratory Investigation, 2022
Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) g... more Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis. As IL-34, a macrophage growth factor, is elevated in RA patients, it is considered a therapeutic target. Unexpectedly, inflammatory arthritis in IL-34 null mice and the newly identified IL-34 receptor, PTPRZ, null mice worsened disease. Through macrophage mediated mechanisms, IL-34 and PTPRZ-dependent events limited apoptotic neutrophil rich synovial inflammation and joint destruction. These findings counter the assumption that IL-34 is harmful in RA, and fuel further studies before designing a therapeutic approach for this illness.
Physiological Reports, 2022
Women mobilize up to 10% of their bone mass during lactation to provide milk calcium. About 8%–13... more Women mobilize up to 10% of their bone mass during lactation to provide milk calcium. About 8%–13% of mothers use selective serotonin reuptake inhibitors (SSRI) to treat peripartum depression, but SSRIs independently decrease bone mass. Previously, peripartal use of the SSRI fluoxetine reduced maternal bone mass sustained post‐weaning and reduced offspring bone length. To determine whether these effects were fluoxetine‐specific or consistent across SSRI compounds, we examined maternal and offspring bone health using the most prescribed SSRI, sertraline. C57BL/6 mice were given 10 mg/kg/day sertraline, from the beginning of pregnancy through the end of lactation. Simultaneously, we treated nulliparous females on the same days as the primiparous groups, resulting in age‐matched nulliparous groups. Dams were euthanized at lactation day 10 (peak lactation, n = 7 vehicle; n = 9 sertraline), lactation day 21 (weaning, n = 9 vehicle; n = 9 sertraline), or 3m post‐weaning (n = 10 vehicle; n = 10 sertraline) for analysis. Offspring were euthanized at peak lactation or weaning for analysis. We determined that peripartum sertraline treatment decreased maternal circulating calcium concentrations across the treatment period, which was also seen in nulliparous treated females. Sertraline reduced the bone formation marker, procollagen 1 intact N‐terminal propeptide, and tended to reduce maternal BV/TV at 3m post‐weaning but did not impact maternal or offspring bone health otherwise. Similarly, sertraline did not reduce nulliparous female bone mass. However, sertraline reduced immunofluorescence staining of the tight junction protein, zona occludens in the mammary gland, and altered alveoli morphology, suggesting sertraline may accelerate mammary gland involution. These findings indicate that peripartum sertraline treatment may be a safer SSRI for maternal and offspring bone rather than fluoxetine.
HAND, 2022
Background: Upper extremity (UE) fragility fractures are common and strong predictors of subseque... more Background: Upper extremity (UE) fragility fractures are common and strong predictors of subsequent fractures. To investigate the relative importance of an UE fragility fracture in determining future fracture risk, we conducted a cross-sectional study to compare future fracture risk between patients presenting for osteoporosis evaluation after an UE fragility fracture and a similarly aged cohort of patients without an UE fracture. Methods: In all, 129 UE fracture patients seen in our bone health clinic (BHC) and 114 non-fracture UE fracture patients seen in an UE clinic completed clinic intake surveys assessing for fracture risk factors. Prefracture fracture risk (PFFR) and fracture risk assessment tool (FRAX) scores estimated the future fracture risks at the timepoint before and after the UE fragility fracture event, respectively. The primary study outcome was the 10-year risk of future fracture. Results: The 10-year probability of major osteoporotic and hip fractures were signific...
ABSTRACTLeucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a marker of osteopr... more ABSTRACTLeucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a marker of osteoprogenitor cells and is dynamically expressed during in vitro osteodifferentation of mouse and human mesenchymal stem cells (MSCs). While the Lgr6 genomic locus has been associated with osteoporosis in human cohorts, the precise molecular function of LGR6 in osteogenesis and maintenance of bone mass are not yet known. In this study, we performed in vitro Lgr6 knockdown and overexpression experiments in murine osteoblastic cells and find decreased Lgr6 levels results in reduced osteoblast proliferation, differentiation, and mineralization. Consistent with these data, overexpression of Lgr6 in these cells leads to significantly increased proliferation and osteodifferentiation. To determine whether these findings are recapitulated in vivo, we performed microCT and ex vivo osteodifferentiation analyses using our newly generated CRISPR-Cas9 mediated Lgr6 mouse knockout allele (Lgr6-KO). We find...
Basic and Applied Bone Biology, 2019
Abstract Osteoimmunology is defined as the study of interactions between the immune and skeletal ... more Abstract Osteoimmunology is defined as the study of interactions between the immune and skeletal systems. The relationship between these systems has been clear for some time given that osteoclasts are derived from immune cells, and that much of the immune system develops within the bone marrow. However, interest in the field was catalyzed by the near simultaneous discovery of the role of the RANK/RANKL system in osteoclastogenesis by both immunologists and bone biologists. Since then, numerous studies have defined molecular interactions between immune and skeletal cells that have demonstrated bidirectional influences between cells from the two systems that regulate development and function of bone and immune responses.
Journal of Clinical Investigation, 2005
Journal of the Endocrine Society, 2021
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidep... more Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressants during pregnancy and lactation. SSRIs decrease bone mineral density (BMD) across all ages and sexes. Lactation is also characterized by increased bone resorption to mobilize calcium and achieves this via a serotonin-induced hormonal cascade. This serotonin-mediated bone loss is normally restored after weaning but is persistent when an SSRI is administered during the peripartum period. Our lab has previously shown that administration of the SSRI fluoxetine (FLX) during both gestation and lactation results in compromised bone health of the dam, which is characterized by a decreased bone mineral density (BMD). Along with this, we have also shown a decrease in BMD and femoral length in the offspring of the FLX-treated dams at weaning. We hypothesize that FLX usage during lactation only will impact the bone health of the dam as well as the bone health of her offspring due to exposure...
Journal of the Endocrine Society, 2021
Lactation taxes mothers’ bone health, causing them to lose up to 10% of their bone mass for milk ... more Lactation taxes mothers’ bone health, causing them to lose up to 10% of their bone mass for milk calcium. Selective serotonin reuptake inhibitor antidepressants (SSRIs) are commonly used during pregnancy and lactation but independently decrease bone mass. We previously demonstrated that both maternal and offspring bone densities were compromised by maternal treatment with the SSRI fluoxetine throughout pregnancy and lactation. In this study, we examined whether sertraline similarly affect maternal and offspring bone. Female C57BL/6 dams (n=23/group) were treated with sertraline (10 mg/kg/d) or a vehicle (DMSO) for 41 d (E0-lactation(L) 21). Pups were euthanized at weaning (L21). Dams were euthanized at peak lactation (L10, n=4/group), weaning (L21, n=9/group) or 3 mo post-weaning (n=10/group) for analysis. Sertraline treatment did not affect dams’ weight gain during pregnancy or lactation and did not impact milk production/consumption, measured by weigh-suckle-weigh. Unlike fluoxeti...
Osteoporosis, 2020
Osteoclasts are multinucleated cells of the myeloid lineage that are highly specialized for bone ... more Osteoclasts are multinucleated cells of the myeloid lineage that are highly specialized for bone resorption through acidification and exocytosis of bone-degrading enzymes into the space between the osteoclast and underlying bone, termed the resorption lacuna. Physiologic osteoclast activity is essential for normal skeletal development and remodeling to repair skeletal microdamage. Osteopetrosis, a collection of monogenic diseases caused by nonfunctional or absent osteoclasts, underscores the importance of adequate osteoclast function for skeletal health. Excessive osteoclastic bone resorption also results in bone disease, including osteoporosis. In this chapter, we provide information on the cellular origin of osteoclasts, discuss the receptors and signaling pathways that drive osteoclast differentiation, and detail the transcriptional machinery required to express the osteoclast program. We detail the cytoskeletal reorganization and formation of a specialized resorption apparatus required for mineral and matrix resorption. Lastly, we discuss the consequences of perturbation of osteoclast formation or function, both in the context of genetic diseases that map to the osteoclast and in the context of pathologic conditions. The goal of this chapter is to provide a detailed overview of osteoclast formation and function that can serve as a reference for clinician’s interested in the role of the osteoclast in osteoporosis.
Blood, 2010
1489 Chronic inflammatory conditions are frequently associated with bone loss. However, the commo... more 1489 Chronic inflammatory conditions are frequently associated with bone loss. However, the common pathways linking these processes are still poorly defined. Here we show that PSTPIP2, an F-BAR domain containing protein, negatively controls inflammation and osteoclast formation. Mutations in Pstpip2 lead to autoinflammatory disease and secondary generalized osteopenia. Dentine disc implants are more rapidly and extensively resorbed in PSTPIP2-deficient mice than in wt controls due to increased osteoclast formation on the implant. Bone marrow and spleens of cmo mice contain increased numbers of multipotent c-Kit+ c-fmslo Mac-1lo myeloid precursors that give rise to more osteoclasts in vitro than cells from wt mice. All these phenotypes are corrected by administration of the CCR1 antagonist BX471. Our results identify PSTPIP2 as an essential limiting factor of myelopoiesis and osteoclast differentiation and MIP-1α as a mediator of inflammation-induced bone loss in PSTPIP-2 deficient m...
Frontiers in Pharmacology, Nov 22, 2023
Proceedings of the National Academy of Sciences of the United States of America, Nov 7, 2016
Journal of the Endocrine Society, May 1, 2021
bioRxiv (Cold Spring Harbor Laboratory), Jan 14, 2020
Elsevier eBooks, 2020
Abstract Bone remodeling occurs through the interactions of two major cell lineages, osteoblasts,... more Abstract Bone remodeling occurs through the interactions of two major cell lineages, osteoblasts, which mediates bone formation, and osteoclasts, which mediate bone resorption. This review provides a through introduction to the myeloid precursors of osteoclasts, the signals that induce their differentiation, the signaling pathways and transcription factors that control their differentiation, fusion and resorptive actions.
Jcr-journal of Clinical Rheumatology, 2011
... Resolution of Recurrent Fusarium Arthritis After Prolonged Antifungal Therapy. Charles, Julia... more ... Resolution of Recurrent Fusarium Arthritis After Prolonged Antifungal Therapy. Charles, Julia F. MD, PhD*; Eberle, Carey MD; Daikh, David I. MD, PhD*; Rooney, Terence MD*. Article Outline. Collapse Box ... Cited Here... 4. Cooke NS, Feighery C, Armstrong DK, et al. ...
HAND
Background: The purpose of this study was to assess the impact of implementation of an outpatient... more Background: The purpose of this study was to assess the impact of implementation of an outpatient fracture liaison service (FLS) on completion rates of dual-energy x-ray absorptiometry (DXA) and screening labs including 25-OH vitamin D and parathyroid hormone (PTH) in patients with upper extremity (UE) fragility fractures. Methods: At our institution, 367 patients were treated in 2014-2015 for UE fragility fractures of the distal radius and proximal humerus before implementation of our outpatient FLS and 395 patients in 2017-2018 after implementation. Retrospective chart review was conducted to identify completed DXA scans within 2 years of fracture treatment and completed 25-OH vitamin D and PTH labs within 1 year of fracture treatment. Results: There were no statistical differences in the demographics of patients treated for distal radial and proximal humeral fragility fractures during the 2014-2015 and 2017-2018 time periods. Implementation of the FLS resulted in a 9.9% increase ...
mSystems
Aging-associated microbial alteration is hypothesized to play an important role in host health an... more Aging-associated microbial alteration is hypothesized to play an important role in host health and longevity. However, investigations regarding specific gut microbes or microbial functional alterations associated with aging have had inconsistent results.
Laboratory Investigation, 2022
Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) g... more Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis. As IL-34, a macrophage growth factor, is elevated in RA patients, it is considered a therapeutic target. Unexpectedly, inflammatory arthritis in IL-34 null mice and the newly identified IL-34 receptor, PTPRZ, null mice worsened disease. Through macrophage mediated mechanisms, IL-34 and PTPRZ-dependent events limited apoptotic neutrophil rich synovial inflammation and joint destruction. These findings counter the assumption that IL-34 is harmful in RA, and fuel further studies before designing a therapeutic approach for this illness.
Physiological Reports, 2022
Women mobilize up to 10% of their bone mass during lactation to provide milk calcium. About 8%–13... more Women mobilize up to 10% of their bone mass during lactation to provide milk calcium. About 8%–13% of mothers use selective serotonin reuptake inhibitors (SSRI) to treat peripartum depression, but SSRIs independently decrease bone mass. Previously, peripartal use of the SSRI fluoxetine reduced maternal bone mass sustained post‐weaning and reduced offspring bone length. To determine whether these effects were fluoxetine‐specific or consistent across SSRI compounds, we examined maternal and offspring bone health using the most prescribed SSRI, sertraline. C57BL/6 mice were given 10 mg/kg/day sertraline, from the beginning of pregnancy through the end of lactation. Simultaneously, we treated nulliparous females on the same days as the primiparous groups, resulting in age‐matched nulliparous groups. Dams were euthanized at lactation day 10 (peak lactation, n = 7 vehicle; n = 9 sertraline), lactation day 21 (weaning, n = 9 vehicle; n = 9 sertraline), or 3m post‐weaning (n = 10 vehicle; n = 10 sertraline) for analysis. Offspring were euthanized at peak lactation or weaning for analysis. We determined that peripartum sertraline treatment decreased maternal circulating calcium concentrations across the treatment period, which was also seen in nulliparous treated females. Sertraline reduced the bone formation marker, procollagen 1 intact N‐terminal propeptide, and tended to reduce maternal BV/TV at 3m post‐weaning but did not impact maternal or offspring bone health otherwise. Similarly, sertraline did not reduce nulliparous female bone mass. However, sertraline reduced immunofluorescence staining of the tight junction protein, zona occludens in the mammary gland, and altered alveoli morphology, suggesting sertraline may accelerate mammary gland involution. These findings indicate that peripartum sertraline treatment may be a safer SSRI for maternal and offspring bone rather than fluoxetine.
HAND, 2022
Background: Upper extremity (UE) fragility fractures are common and strong predictors of subseque... more Background: Upper extremity (UE) fragility fractures are common and strong predictors of subsequent fractures. To investigate the relative importance of an UE fragility fracture in determining future fracture risk, we conducted a cross-sectional study to compare future fracture risk between patients presenting for osteoporosis evaluation after an UE fragility fracture and a similarly aged cohort of patients without an UE fracture. Methods: In all, 129 UE fracture patients seen in our bone health clinic (BHC) and 114 non-fracture UE fracture patients seen in an UE clinic completed clinic intake surveys assessing for fracture risk factors. Prefracture fracture risk (PFFR) and fracture risk assessment tool (FRAX) scores estimated the future fracture risks at the timepoint before and after the UE fragility fracture event, respectively. The primary study outcome was the 10-year risk of future fracture. Results: The 10-year probability of major osteoporotic and hip fractures were signific...
ABSTRACTLeucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a marker of osteopr... more ABSTRACTLeucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a marker of osteoprogenitor cells and is dynamically expressed during in vitro osteodifferentation of mouse and human mesenchymal stem cells (MSCs). While the Lgr6 genomic locus has been associated with osteoporosis in human cohorts, the precise molecular function of LGR6 in osteogenesis and maintenance of bone mass are not yet known. In this study, we performed in vitro Lgr6 knockdown and overexpression experiments in murine osteoblastic cells and find decreased Lgr6 levels results in reduced osteoblast proliferation, differentiation, and mineralization. Consistent with these data, overexpression of Lgr6 in these cells leads to significantly increased proliferation and osteodifferentiation. To determine whether these findings are recapitulated in vivo, we performed microCT and ex vivo osteodifferentiation analyses using our newly generated CRISPR-Cas9 mediated Lgr6 mouse knockout allele (Lgr6-KO). We find...
Basic and Applied Bone Biology, 2019
Abstract Osteoimmunology is defined as the study of interactions between the immune and skeletal ... more Abstract Osteoimmunology is defined as the study of interactions between the immune and skeletal systems. The relationship between these systems has been clear for some time given that osteoclasts are derived from immune cells, and that much of the immune system develops within the bone marrow. However, interest in the field was catalyzed by the near simultaneous discovery of the role of the RANK/RANKL system in osteoclastogenesis by both immunologists and bone biologists. Since then, numerous studies have defined molecular interactions between immune and skeletal cells that have demonstrated bidirectional influences between cells from the two systems that regulate development and function of bone and immune responses.
Journal of Clinical Investigation, 2005
Journal of the Endocrine Society, 2021
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidep... more Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressants during pregnancy and lactation. SSRIs decrease bone mineral density (BMD) across all ages and sexes. Lactation is also characterized by increased bone resorption to mobilize calcium and achieves this via a serotonin-induced hormonal cascade. This serotonin-mediated bone loss is normally restored after weaning but is persistent when an SSRI is administered during the peripartum period. Our lab has previously shown that administration of the SSRI fluoxetine (FLX) during both gestation and lactation results in compromised bone health of the dam, which is characterized by a decreased bone mineral density (BMD). Along with this, we have also shown a decrease in BMD and femoral length in the offspring of the FLX-treated dams at weaning. We hypothesize that FLX usage during lactation only will impact the bone health of the dam as well as the bone health of her offspring due to exposure...
Journal of the Endocrine Society, 2021
Lactation taxes mothers’ bone health, causing them to lose up to 10% of their bone mass for milk ... more Lactation taxes mothers’ bone health, causing them to lose up to 10% of their bone mass for milk calcium. Selective serotonin reuptake inhibitor antidepressants (SSRIs) are commonly used during pregnancy and lactation but independently decrease bone mass. We previously demonstrated that both maternal and offspring bone densities were compromised by maternal treatment with the SSRI fluoxetine throughout pregnancy and lactation. In this study, we examined whether sertraline similarly affect maternal and offspring bone. Female C57BL/6 dams (n=23/group) were treated with sertraline (10 mg/kg/d) or a vehicle (DMSO) for 41 d (E0-lactation(L) 21). Pups were euthanized at weaning (L21). Dams were euthanized at peak lactation (L10, n=4/group), weaning (L21, n=9/group) or 3 mo post-weaning (n=10/group) for analysis. Sertraline treatment did not affect dams’ weight gain during pregnancy or lactation and did not impact milk production/consumption, measured by weigh-suckle-weigh. Unlike fluoxeti...
Osteoporosis, 2020
Osteoclasts are multinucleated cells of the myeloid lineage that are highly specialized for bone ... more Osteoclasts are multinucleated cells of the myeloid lineage that are highly specialized for bone resorption through acidification and exocytosis of bone-degrading enzymes into the space between the osteoclast and underlying bone, termed the resorption lacuna. Physiologic osteoclast activity is essential for normal skeletal development and remodeling to repair skeletal microdamage. Osteopetrosis, a collection of monogenic diseases caused by nonfunctional or absent osteoclasts, underscores the importance of adequate osteoclast function for skeletal health. Excessive osteoclastic bone resorption also results in bone disease, including osteoporosis. In this chapter, we provide information on the cellular origin of osteoclasts, discuss the receptors and signaling pathways that drive osteoclast differentiation, and detail the transcriptional machinery required to express the osteoclast program. We detail the cytoskeletal reorganization and formation of a specialized resorption apparatus required for mineral and matrix resorption. Lastly, we discuss the consequences of perturbation of osteoclast formation or function, both in the context of genetic diseases that map to the osteoclast and in the context of pathologic conditions. The goal of this chapter is to provide a detailed overview of osteoclast formation and function that can serve as a reference for clinician’s interested in the role of the osteoclast in osteoporosis.
Blood, 2010
1489 Chronic inflammatory conditions are frequently associated with bone loss. However, the commo... more 1489 Chronic inflammatory conditions are frequently associated with bone loss. However, the common pathways linking these processes are still poorly defined. Here we show that PSTPIP2, an F-BAR domain containing protein, negatively controls inflammation and osteoclast formation. Mutations in Pstpip2 lead to autoinflammatory disease and secondary generalized osteopenia. Dentine disc implants are more rapidly and extensively resorbed in PSTPIP2-deficient mice than in wt controls due to increased osteoclast formation on the implant. Bone marrow and spleens of cmo mice contain increased numbers of multipotent c-Kit+ c-fmslo Mac-1lo myeloid precursors that give rise to more osteoclasts in vitro than cells from wt mice. All these phenotypes are corrected by administration of the CCR1 antagonist BX471. Our results identify PSTPIP2 as an essential limiting factor of myelopoiesis and osteoclast differentiation and MIP-1α as a mediator of inflammation-induced bone loss in PSTPIP-2 deficient m...