Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

Abstract

Augmenting peak bone mass is a promising strategy to prevent osteoporosis. A mouse model of global progesterone receptor (PR) ablation showed increased bone mass through a sex-dependent mechanism. Cre-Lox recombination was used to generate a mouse model of osteoprogenitor specific PR inactivation, which recapitulated the high bone mass phenotype. In this work, we employed RNA sequencing analysis to evaluate sex-independent and sex-dependent differences in gene transcription of osteoprogenitors of wild type and PR conditional knockout mice. PR deletion caused marked sex hormone-dependent changes in gene transcription in male mice as compared to wild-type controls. These transcriptional differences revealed dysregulation in pathways involving immunomodulation, osteoclasts, bone anabolism, extracellular matrix interaction, and matrix interaction. These results identified many potential mechanisms that may explain our observed high bone mass phenotype with sex differences when PR was selectively deleted in the MSCs.

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells

“…We and others have found PR expressed in growth plate chondrocytes, osteoclasts, and osteoblasts, and PR plays a critical role in peak bone mass determination [37, 71,72]. We also have reported that the loss of PR signaling in osteoprogenitor cells regulates key signaling pathways for immune response, especially in males [34].…”

“…Additionally, conditional PR deletion in the Prx1 + osteoprogenitor cells significantly suppressed immunomodulatory pathways, especially in the males. The disease pathway analyses from our previous RNA-Seq study suggested that rheumatoid arthritis is a most-likely targeted disease for PR [34]. which prompted further evaluation of the role of PR in the pathogenesis of RA in this current study.…”

“…The right knee joints including both the distal femurs (DFM) and the proximal tibiae were scanned and analyzed using VivaCT 40 (Scanco Medical, Bassersdorf Switzerland) with a voxel resolution of 10 µm in all three spatial dimensions and a mono-energetic (70 Kev) X-ray source. We evaluated the entire knee covering a total of 645 mm in length centered around the knee joint to obtain total knee bone volume/tissue volume (BV/TV) ratio [34,51,52] using 3D image-registration schemes Gaussian filters of sigma = 0.8, support = 1 and threshold = 180 for total knee and DFM. Gaussian filters of sigma = 1, support = 2, and threshold = 280 were applied to register the paw.…”

“…The presence or absence or relative proportion of PR in different tissues may explain the PR's sex dimorphic roles in these tissues [29][30][31]. In contrast to the estrogen receptor, PR's role may be more important in immunomodulation in female-dominant diseases such as systemic lupus erythematosus, rheumatoid arthritis, and osteoarthritis [32][33][34]. However, PR as an immunomodulatory regulator in musculoskeletal tissue is not well understood.…”

“…which prompted further evaluation of the role of PR in the pathogenesis of RA in this current study. Since we observed the lack of PR signaling in OPC significantly regulated pathways involved in immunomodulation pathways previously [34], we set to perform this follow-up study in the PR ΔPrx1 mice using a CIA model. Total mononuclear cells were collected from peripheral blood using the Ficoll-Paque density gradient method.…”