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  • eLife Sciences Publications, Ltd  (13)
  • 1
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    Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption
    eLife Sciences Publications, Ltd ; 2021
    In:  eLife Vol. 10 ( 2021-06-23)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 10 ( 2021-06-23)
    Abstract: Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05–099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05–099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05–099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05–099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05–099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.67772
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2021
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  • 2
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    FSH-blocking therapeutic for osteoporosis
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-09-20)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-09-20)
    Abstract: Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer’s disease. Blocking FSH action prevents bone loss, fat gain, and neurodegeneration in mice. We recently developed a first-in-class, humanized, epitope-specific FSH-blocking antibody, MS-Hu6, with a K D of 7.52 nM. Using a Good Laboratory Practice (GLP)-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using 89 Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t ½ of 7.5 days (180 hr) in humanized Tg32 mice. We tested 217 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. The MS-Hu6 showed the same level of “humanness” as human IgG1 in silico and was non-immunogenic in ELISpot assays for IL-2 and IFN-γ in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable, and manufacturable, and is therefore poised for future human testing.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.78022
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
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  • 3
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    MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-05-25)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-05-25)
    Abstract: MAF1, a key repressor of RNA polymerase (pol) III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show that MAF1 plays a critical role in regulating osteoblast differentiation and bone mass. Global deletion of MAF1 ( Maf1 -/- mice) produced a high bone mass phenotype. However, osteoblasts isolated from Maf1 -/- mice showed reduced osteoblastogenesis ex vivo. Therefore, we determined the phenotype of mice overexpressing MAF1 in cells from the mesenchymal lineage ( Prx1 -Cre;LSL- MAF1 mice). These mice showed increased bone mass. Ex vivo, cells from these mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1 -/- mice is likely due to confounding effects from the global absence of MAF1. MAF1 overexpression promoted osteoblast differentiation of ST2 cells while MAF1 downregulation inhibited differentiation, indicating MAF1 enhances osteoblast formation. However, other perturbations used to repress RNA pol III transcription, inhibited osteoblast differentiation. However, decreasing RNA pol III transcription through these perturbations enhanced adipogenesis in ST2 cells. RNA-seq analyzed the basis for these opposing actions on osteoblast differentiation. The different modalities used to perturb RNA pol III transcription resulted in distinct gene expression changes, indicating that this transcription process is highly sensitive and triggers diverse gene expression programs and phenotypic outcomes. Specifically, MAF1 induced genes known to promote osteoblast differentiation. Furthermore, genes that are induced during osteoblast differentiation displayed codon bias. Together, these results reveal a novel role for MAF1 and RNA pol III-mediated transcription in osteoblast fate determination, differentiation, and bone mass regulation.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.74740
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
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  • 4
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    Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo
    eLife Sciences Publications, Ltd ; 2020
    In:  eLife Vol. 9 ( 2020-08-11)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 9 ( 2020-08-11)
    Abstract: Irisin, a skeletal-muscle secreted myokine, facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In this study, we investigated whether irisin directly regulates osteoclasts. In vitro, irisin (2–10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; however, this increase was blocked by a neutralizing antibody to integrin α V β 5 . Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating ‘clastokines’. Forced expression of the irisin precursor Fndc5 in transgenic C57BL/6J mice resulted in lower bone mass at three ages and greater in vitro osteoclastogenesis from Fndc5 -transgenic bone marrow progenitors. This study demonstrates that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption, supporting the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.58172
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2020
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  • 5
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    Development and biophysical characterization of a humanized FSH–blocking monoclonal antibody therapeutic formulated at an ultra-high concentration
    eLife Sciences Publications, Ltd ; 2023
    In:  eLife Vol. 12 ( 2023-06-19)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2023-06-19)
    Abstract: Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the development of a unique formulation for our first-in-class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer’s disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation’s long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, confirmed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) Spectroscopy. Three rapid freeze–thaw cycles at –80 °C/25 °C or –80 °C/37 °C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (T m ) for formulated MS-Hu6 increased by 〉 4.80 °C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.88898
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2023
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  • 6
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    Deletion of FNDC5/irisin modifies murine osteocyte function in a sex-specific manner
    eLife Sciences Publications, Ltd ; 2024
    In:  eLife Vol. 12 ( 2024-04-25)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2024-04-25)
    Abstract: Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low-calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.92263.3
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2024
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  • 7
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    Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-06-22)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-06-22)
    Abstract: To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2 gene). BMAd- Pnpla2 -/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone in male mice, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.78496
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
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  • 8
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    Bone circuitry and interorgan skeletal crosstalk
    eLife Sciences Publications, Ltd ; 2023
    In:  eLife Vol. 12 ( 2023-01-19)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2023-01-19)
    Abstract: The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.83142
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2023
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  • 9
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    Brain atlas for glycoprotein hormone receptors at single-transcript level
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-09-02)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-09-02)
    Abstract: There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHR, LHCGR, and FSHR. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and subnuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates . We also identified Lhcgr transcripts in 401 brain regions, nuclei and subnuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHR in human brain samples, where transcripts were co-localized in MALAT1 -positive neurons. In addition, we show high expression for all three receptors in the ventricular region—with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. In contrast, Fshr was localized to NeuN-positive neurons in the granular layer of the dentate gyrus in murine and human brain—both are Alzheimer’s disease-vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.79612
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
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  • 10
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    Deletion of FNDC5/irisin modifies murine osteocyte function in a sex-specific manner
    eLife Sciences Publications, Ltd ; 2024
    In:  eLife Vol. 12 ( 2024-04-25)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2024-04-25)
    Abstract: Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low-calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.92263
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2024
    detail.hit.zdb_id: 2687154-3
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