Blocking the movement of cells from the bone marrow by inhibiting the CXCL12/CXCR4/CXCR7 signaling axis is a potential strategy for treating endometriosis, a recent study done in mice suggests.
The study, titled “CXCR4 or CXCR7 antagonists treat endometriosis by reducing bone marrow cell trafficking,” was published in the Journal of Cellular and Molecular Medicine.
Bone marrow-derived cells (BMDCs) play important roles in the normal functioning of the endometrium. For instance, stem cells from the bone marrow are involved in endometrial regeneration. But BMDCs also are involved in the formation of lesions in endometriosis.
The movement of BMDCs to uterine tissue — whether for normal physiological reasons or as part of disease development — is driven in large part by the signaling protein CXCL12. It acts through two protein receptors: CXCR4 and CXCR7. This CXCL12/CXCR4/CXCR7 signaling axis has been shown to be overactive in women with endometriosis.
“Given the central role of the CXCL12/CXCR4/CXCR7 axis on BMDCs trafficking and in the pathogenesis [development] of endometriosis, we hypothesized that blocking CXCR4 or CXCR7 in endometriosis … would inhibit the growth of endometriosis,” the researchers said.
The scientists first used mouse models of endometriosis in which BMDCs were labeled with a fluorescent marker to confirm the presence of these cells in endometriotic lesions.
The BMDCs made up just over 10% of the total number of cells in lesions. Further, BMDCs that expressed CXCR4 represented about 4.4% of total lesion cells, while BMDCs expressing CXCR7 made up about 1.4%. CXCL12 also was highly expressed within the lesions.
The researchers then pharmacologically blocked each of the receptors, using Plerixafor (AMD3100) against CXCR4, and CCX771 against CXCR7. Plerixafor is used in stem cell transplants given to treat certain types of blood cancer. CCX771 is a small molecule without currently approved clinical uses.
Both treatments significantly reduced the percentage of BMDCs in lesions, suggesting that blocking this signaling axis did indeed stop the movement of these cells.
In addition, when either Plerixafor or CCX771 was given immediately after endometriosis establishment, the size of the endometriotic lesions was reduced by more than half compared with control mice. Blood vessel density also was significantly reduced, by about 40% for both receptors.
The treatments also reduced the expression of inflammatory signaling molecules known to be elevated in endometriosis, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF‐alpha).
In a separate experiment to further test the treatment’s potential, Plerixafor and CCX771 were administered a few weeks after the endometriosis lesions developed. “This more closely models the pre‐existing lesions found in humans at the time of endometriosis diagnosis,” the researchers said.
The results were similar to those seen in the earlier model: there were significant decreases in lesion size— by about 60% — as well as in levels of inflammatory signaling molecules.
Notably, neither drug had any detectable effect on hormone cycling in the mice, “demonstrating that the effects of these agents worked [through] a hormone independent pathway,” the researchers said.
Based on the data, the researchers concluded that blocking the CXCL12/CXCR4/CXCR7 signaling axis may treat endometriosis. However, these results alone do not demonstrate that this effect is directly because of reduced BMDC recruitment. It would be equally plausible to postulate that the effect is due to blocking CXCL12/CXCR4/CXCR7 signaling in the endometrial cells themselves, not BMDCs, the investigators said.
To test this idea, the team established endometriosis models in mice that were engineered so that the cells in their uteruses could not make CXCL12. There were no detectable differences between these endometriosis lesions and lesions in mice that could make CXCL12 in their uteruses. Further, Plerixafor had no detectable effect on human endometrial cells taken from people with endometriosis and treated in a dish.
This suggests that the beneficial effect induced by blocking CXCL12/CXCR4/CXCR7 signaling is due to an effect on cells outside of the uterus. Due to their prevalence in lesions, this most likely means BMDCs, the researchers said.
“Clinical use [of these therapies] will likely depend on side effect profile; the effects of prolonged use are not well characterized,” the team said. They added that future studies evaluating such drugs’ safety profiles and off-target effects, particularly with long-term use, will be needed before these results can be translated into clinical application.
“CXCR4 and CXCR7 antagonists are promising novel, non‐hormonal therapies for endometriosis,” the researchers concluded.