We compared the effects of a nitrogen-containing bisphosphonate (N-BP), zoledronic acid (ZA), and an anti-mouse RANKL antibody (anti-mRANKL Ab) on the bone tissue pathology of a transgenic mouse ...model of human fibrous dysplasia (FD). For comparison, we also reviewed the histological samples of a child with McCune–Albright syndrome (MAS) treated with Pamidronate for 3 years. EF1α-Gsα
R201C
mice with FD-like lesions in the tail vertebrae were treated with either 0.2 mg/kg of ZA at day 0, 7, and 14 or with 300 μg/mouse of anti-mRANKL Ab at day 0 and 21. All mice were monitored by Faxitron and histological analysis was performed at day 42. ZA did not affect the progression of the radiographic phenotype in EF1α-Gsα
R201C
mice. FD-like lesions in the ZA group showed the persistence of osteoclasts, easily detectable osteoclast apoptotic activity and numerous “giant osteoclasts”. In contrast, in the anti-mRANKL Ab-treated mice, osteoclasts were markedly reduced/absent, the radiographic phenotype reverted and the FD-like lesions were extensively replaced by newly formed bone. Numerous “giant osteoclasts” were also detected in the samples of the child with MAS. This study supports the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The interest in bone marrow adiposity (BMA) has increased over the last decade due to its association with, and potential role, in a range of diseases (osteoporosis, diabetes, anorexia, cancer) as ...well as treatments (corticosteroid, radiation, chemotherapy, thiazolidinediones). However, to advance the field of BMA research, standardization of methods is desirable to increase comparability of study outcomes and foster collaboration. Therefore, at the 2017 annual BMA meeting, the International Bone Marrow Adiposity Society (BMAS) founded a working group to evaluate methodologies in BMA research. All BMAS members could volunteer to participate. The working group members, who are all active preclinical or clinical BMA researchers, searched the literature for articles investigating BMA and discussed the results during personal and telephone conferences. According to the consensus opinion, both based on the review of the literature and on expert opinion, we describe existing methodologies and discuss the challenges and future directions for (1) histomorphometry of bone marrow adipocytes, (2)
BMA imaging, (3)
BMA imaging, (4) cell isolation, culture, differentiation and
modulation of primary bone marrow adipocytes and bone marrow stromal cell precursors, (5) lineage tracing and
BMA modulation, and (6) BMA biobanking. We identify as accepted standards in BMA research: manual histomorphometry and osmium tetroxide 3D contrast-enhanced μCT for
quantification, specific MRI sequences (WFI and H-MRS) for
studies, and RT-qPCR with a minimal four gene panel or lipid-based assays for
quantification of bone marrow adipogenesis. Emerging techniques are described which may soon come to complement or substitute these gold standards. Known confounding factors and minimal reporting standards are presented, and their use is encouraged to facilitate comparison across studies. In conclusion, specific BMA methodologies have been developed. However, important challenges remain. In particular, we advocate for the harmonization of methodologies, the precise reporting of known confounding factors, and the identification of methods to modulate BMA independently from other tissues. Wider use of existing animal models with impaired BMA production (e.g.,
, Kit
) and development of specific BMA deletion models would be highly desirable for this purpose.
The first International Summer School on Bone Marrow Adiposity was organized by members of Bone Marrow Adiposity Society and held virtually on September 6-8 2021. The goal of this meeting was to ...bring together young scientists interested in learning about bone marrow adipose tissue biology and pathology. Fifty-two researchers from different backgrounds and fields, ranging from bone physiopathology to adipose tissue biology and hematology, participated in the summer school. The meeting featured three keynote lectures on the fundamentals of bone marrow adiposity, three scientific workshops on technical considerations in studying bone marrow adiposity, and six motivational and career development lectures, spanning from scientific writing to academic career progression. Moreover, twenty-one participants presented their work in the form of posters. In this report we highlight key moments and lessons learned from the event.
The Gsα/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsα due to ...gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsα have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression of Gsα
driven by the Adiponectin (Adq) promoter. Adq-Gsα
mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, Gsα
caused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced by Adq-Cre and eventually resulted in a high trabecular bone mass phenotype. In the diaphysis, Gsα
, in combination with estrogen, triggered the osteogenic activity of Adq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence of Adq-Cre-marked pericytes in intraosseous blood vessels, Gsα
caused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that the Adq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsα/cAMP pathway is a major modulator of both functions.
Age‐associated alterations of the hormone‐secreting endocrine system cause organ dysfunction and disease states. However, the cell biology of endocrine tissue ageing remains poorly understood. Here, ...we perform comparative 3D imaging to understand age‐related perturbations of the endothelial cell (EC) compartment in endocrine glands. Datasets of a wide range of markers highlight a decline in capillary and artery numbers, but not of perivascular cells in pancreas, testis and thyroid gland, with age in mice and humans. Further, angiogenesis and β‐cell expansion in the pancreas are coupled by a distinct age‐dependent subset of ECs. While this EC subpopulation supports pancreatic β cells, it declines during ageing concomitant with increased expression of the gap junction protein Gja1. EC‐specific ablation of Gja1 restores β‐cell expansion in the aged pancreas. These results provide a proof of concept for understanding age‐related vascular changes and imply that therapeutic targeting of blood vessels may restore aged endocrine tissue function. This comprehensive data atlas offers over > 1,000 multicolour volumes for exploration and research in endocrinology, ageing, matrix and vascular biology.
Synopsis
Despite the pathophysiological consequences of age‐dependent hormonal perturbations, endocrine organ alterations during ageing remain poorly understood. This systematic imaging atlas unveils age‐associated endocrine perturbations by characterizing endothelial cells (EC) and blood vessels in young versus old hormone‐secreting glands.
High‐resolution imaging of > 60 EC and matrix markers defines the vasculature in adrenal gland, ovary, pituitary gland, testis, pancreas and thyroid gland.
Capillary and artery numbers decline during ageing in mouse and human.
A CD31posEmcnhighESM‐1low pancreatic islet EC subpopulation supports beta‐cell proliferation but decreases during ageing.
EC‐specific ablation of age‐increased gap junction protein Gja1 rescues vessel growth in the pancreas.
Single‐cell‐resolution 3D imaging unveils organ‐based specialisation and age‐related changes in the vasculature of hormone‐secreting glands.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Loss of the 9p21-syntenic locus in mice causes MDS/MPN–like disease with BM fibrosis and/or ossification.•The disease is driven by the aberrant BM niche producing less CXCL12 and more CXCL13 and ...osteopontin.
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The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A, and CDKN2B, and its homo- or heterozygous deletion is associated with reduced survival in multiple cancer types. We report that mice with germ line monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the profibrotic chemokine Cxcl13 and the osteogenesis- and fibrosis-related multifunctional glycoprotein osteopontin/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN–like disease.
Deletion of chromosome 9p21 is associated with reduced survival in many cancers. Feng et al report that heterozygous deletion of the syntenic region in a mouse model leads to myelodysplastic syndrome/myeloproliferative neoplasm–like disease with marrow fibrosis and/or trabecular bone abnormalities. Using reciprocal transplants, the authors demonstrate that the changes are governed by the marrow microenvironment, highlighting a potential entry point for investigation of targeted therapy for myelofibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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