Intrinsic Sex‐Linked Variations in Osteogenic and Adipogenic Differentiation Potential of Bone Marrow Multipotent Stromal Cells

Abstract

Bone formation and aging are sexually dimorphic. Yet, definition of the intrinsic molecular differences between male and female multipotent mesenchymal stromal cells (MSC) in bone is lacking. This study assessed sex-linked differences in MSC differentiation in 3-, 6-, and 9-month-old C57BL/6J mice. Analysis of tibiae showed that female mice had lower bone volume fraction and higher adipocyte content in the bone marrow compared to age-matched males. While both males and females lost bone mass in early aging, the rate of loss was higher in males. Similar expression of bone- and adipocyte-related genes was seen in males and females at 3 and 9 months, while at 6 months, females exhibited a two-fold greater expression of these genes. Under osteogenic culture conditions, bone marrow MSCs from female 3- and 6-month-old mice expressed similar levels of bone-related genes, but significantly greater levels of adipocyte-related genes, than male MSCs. Female MSCs also responded to rosiglitazone-induced suppression of osteogenesis at a 5-fold lower (10 nM) concentration than male MSCs. Female MSCs grown in estrogen-stripped medium showed similar responses to rosiglitazone as MSCs grown in serum containing estrogen. MSCs from female mice that had undergone ovariectomy before sexual maturity also were sensitive to rosiglitazone-induced effects on osteogenesis. These results suggest that female MSCs are more sensitive to modulation of differentiation by PPARγ and that these differences are intrinsic to the sex of the animal from which the MSCs came. These results also may explain the sensitivity of women to the deleterious effects of rosiglitazone on bone.

Microbiota Reconstitution Does Not Cause Bone Loss in Germ-Free Mice

“…Sex differences have been shown to impact various facets of bone metabolism ( 25 – 27 ). Previous studies on the role of the gut microbiota in bone density examined female mice ( 19 ).…”

Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

“…PLIN1, ATGL and MEDA-4[85, 86]) and the effect of genetic deletion of SERT[87], GPER[88] and CD24[89] on adipogenesis in mice is gender dependent. The mechanisms for this difference appears to be complex including differential sensitivity to activation of the adipogenic transcription factor PPARG[90] and to differences in tissue microenvironments. For example, the balance between TIMP4 and MMP3 expression, which differs in males and females[91], is critical for remodeling the microenvironment to permit adipocyte proliferation.…”

Primary osteoblasts, osteoblast precursor cells or osteoblast‐like cell lines: Which human cell types are (most) suitable for characterizing 45S5‐bioactive glass?

“…Cell line derived from a 15-year-old female Caucasian osteosarcoma patient (Rousseau, Lamoureux et al 2010). Furthermore, it was demonstrated that these cell lines show significant differences in proliferation patterns (Lauvrak et al, 2013 (Bragdon et al, 2015;Friedl et al, 2007;Friedman, Long, & Hankenson, 2006;Widholz et al, 2019). Furthermore, it was demonstrated that these cell lines show significant differences in proliferation patterns (Lauvrak et al, 2013 (Bragdon et al, 2015;Friedl et al, 2007;Friedman, Long, & Hankenson, 2006;Widholz et al, 2019).…”

“…However, since primary cells are prone to variance caused by the donor patient (comorbidities, sex, age, etc. ), transferability of study results is limited, thus the donor patients' individual characteristics have to be considered (Bragdon et al, 2015;Friedl et al, 2007;Friedman, Long, & Hankenson, 2006;Widholz et al, 2019).…”