Sex and Genetic Factors Determine Osteoblastic Differentiation Potential of Murine Bone Marrow Stromal Cells

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Abstract

Sex and genetic factors determine skeletal mass, and we tested whether bone histomorphometric parameters were sexually dimorphic in femurs from 1 to 6 month old C57BL/6 mice. Trabecular bone volume declined more rapidly in female mice than in male littermates because of enhanced bone resorption. Although bone formation was not different between sexes, female mice exhibited a higher number of osteoblasts than male littermates, suggesting that osteoblasts from female mice may have a reduced ability to form bone. To determine the impact of sex on osteoblastogenesis, we investigated the potential for osteoblastic differentiation of bone marrow stromal cells from C57BL/6, Friend leukemia virus-B (FVB), C3H/HeJ and BALB/c mice of both sexes. Bone marrow stromal cells from female FVB, C57BL/6 and C3H/HeJ mice exhibited lower Alpl and Osteocalcin expression and alkaline phosphatase activity, and formed fewer mineralized nodules than cells from male littermates. Proliferative capacity was greater in cells from male than female C57BL/6, but not FVB, mice. Sorting of bone marrow stromal cells from mice expressing an α-Smooth muscle actin-green fluorescent protein transgene, revealed a higher yield of mesenchymal stem cells in cultures from male mice than in those from female littermates. Sex had a modest impact on osteoblastic differentiation of mesenchymal stem cells. To determine the influence of sex and genetic factors on osteoblast function, calvarial osteoblasts were harvested from C57BL/6, FVB, C3H/HeJ and BALB/c mice. Alpl expression and activity were lower in osteoblasts from C57BL/6 and C3H/HeJ, but not FVB or BALB/c, female mice than in cells from littermates. Sex had no effect on osteoclastogenesis of bone marrow cultures of C57BL/6 mice, but osteoblasts from female mice exhibited higher Rankl and lower Opg expression than cells from male littermates. In conclusion, osteoblastogenesis is sexually dimorphic and influenced by genetic factors.

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Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration.

Dongsu Park, Joel A. Spencer, Bong Ihn Koh … (2012)

Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have entered clinical application despite little definition of their function in residence. Here, we report genetic pulse-chase experiments that define osteoblastic cells as short-lived and nonreplicative, requiring replenishment from bone-marrow-derived, Mx1(+) stromal cells with "MSC" features. These cells respond to tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing. Single cell transplantation yielded progeny that both preserve progenitor function and differentiate into osteoblasts, producing new bone. They are capable of local and systemic translocation and serial transplantation. While these cells meet current definitions of MSCs in vitro, they are osteolineage restricted in vivo in growing and adult animals. Therefore, bone-marrow-derived MSCs may be a heterogeneous population with the Mx1(+) population, representing a highly dynamic and stress responsive stem/progenitor cell population of fate-restricted potential that feeds the high cell replacement demands of the adult skeleton. Copyright Â© 2012 Elsevier Inc. All rights reserved.

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Age-related changes in trabecular architecture differ in female and male C57BL/6J mice.

Vaida Glatt, Ernesto Canalis, Lisa Stadmeyer … (2007)

We used microCT and histomorphometry to assess age-related changes in bone architecture in male and female C57BL/6J mice. Deterioration in vertebral and femoral trabecular microarchitecture begins early, continues throughout life, is more pronounced at the femoral metaphysis than in the vertebrae, and is greater in females than males. Despite widespread use of mice in the study of musculoskeletal disease, the age-related changes in murine bone structure and the relationship to whole body BMD changes are not well characterized. Thus, we assessed age-related changes in body composition, whole body BMD, and trabecular and cortical microarchitecture at axial and appendicular sites in mice. Peripheral DXA was used to assess body composition and whole body BMD in vivo, and microCT and histomorphometry were used to measure trabecular and cortical architecture in excised femora, tibia, and vertebrae in male and female C57BL/6J mice at eight time-points between 1 and 20 mo of age (n = 6-9/group). Body weight and total body BMD increased with age in male and female, with a marked increase in body fat between 6 and 12 mo of age. In contrast, trabecular bone volume (BV/TV) was greatest at 6-8 wk of age and declined steadily thereafter, particularly in the metaphyseal region of long bones. Age-related declines in BV/TV were greater in female than male. Trabecular bone loss was characterized by a rapid decrease in trabecular number between 2 and 6 mo of age, and a more gradual decline thereafter, whereas trabecular thickness increased slowly over life. Cortical thickness increased markedly from 1 to 3 mo of age and was maintained or slightly decreased thereafter. In C57BL/6J mice, despite increasing body weight and total body BMD, age-related declines in vertebral and distal femoral trabecular bone volume occur early and continue throughout life and are more pronounced in females than males. Awareness of these age-related changed in bone morphology are critical for interpreting the skeletal response to pharmacologic interventions or genetic manipulation in mice.

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Osteoclasts: what do they do and how do they do it?

Steven Teitelbaum (2007)

As Americans live longer, degenerative skeletal diseases, such as osteoporosis, become increasingly prevalent. Regardless of cause, osteoporosis reflects a relative enhancement of osteoclast activity. Thus, this unique bone resorptive cell is a prominent therapeutic target. A number of key observations provide insights into the mechanisms by which precursors commit to the osteoclast phenotype and how the mature cell degrades bone. The osteoclast is a member of the monocyte/macrophage family that differentiates under the aegis of two critical cytokines, namely RANK ligand and M-CSF. Tumor necrosis factor (TNF)-alpha also promotes osteoclastogenesis, particularly in states of inflammatory osteolysis such as that attending rheumatoid arthritis. Once differentiated, the osteoclast forms an intimate relationship with the bone surface via the alphavbeta3 integrin, which transmits matrix-derived, cytoskeleton-organizing, signals. These integrin-transmitted signals include activation of the associated proteins, c-src, syk, Vav3, and Rho GTPases. The organized cytoskeleton generates an isolated microenvironment between the cell's plasma membrane and the bone surface in which matrix mineral is mobilized by the acidic milieu and organic matrix is degraded by the lysosomal protease, cathepsin K. This review focuses on these and other molecules that mediate osteoclast differentiation or function and thus serve as candidate anti-osteoporosis therapeutic targets.

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Author and article information

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Luc Malaval: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 28 January 2014

Volume: 9

Issue: 1

Electronic Location Identifier: e86757

Affiliations

[1 ]Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut, United States of America

[2 ]University of Connecticut School of Medicine, University of Connecticut Health Center, Farmington, Connecticut, United States of America

[3 ]Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, Connecticut, United States of America

[4 ]Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, United States of America

INSERM U1059/LBTO, Université Jean Monnet, France

Author notes

* E-mail: szanotti@ 123456stfranciscare.org

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SZ IK HLA EC. Performed the experiments: SZ IK HLA. Analyzed the data: SZ IK HLA EC. Contributed reagents/materials/analysis tools: IK HLA EC. Wrote the paper: SZ EC.

Article

Publisher ID: PONE-D-13-31354

DOI: 10.1371/journal.pone.0086757

PMC ID: 3904935

PubMed ID: 24489784

SO-VID: 9c34db29-fe21-4830-a21d-aa548be407c9

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 August 2013

Date accepted : 16 December 2013

Page count

Pages: 13

Funding

Research reported in this publication was supported by a Research Fellowship from the Arthritis Foundation ( http://www.arthritis.org/), under Award Number 5371 (S.Z.), Grant from the National Institute of Diabetes, Digestive and Kidney Diseases, under Award Number DK045227 (E.C.), Grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases, under Award Number AR021707, AR063049 (E.C.) and AR055607 (I.K.) and Grant from the National Heart, Lung, and Blood Institute, under Award Number HL100569 (H.L.A.), all part of the National Institutes of Health ( http://www.nih.gov/). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Sex and Genetic Factors Determine Osteoblastic Differentiation Potential of Murine Bone Marrow Stromal Cells

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Abstract

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Most cited references 40

Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration.

Age-related changes in trabecular architecture differ in female and male C57BL/6J mice.

Osteoclasts: what do they do and how do they do it?

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