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TGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice

TGFβ1 induces age-related bone loss by promoting degradation of TNF receptor-associated factor 3 (TRAF3), levels of which decrease in murine and human bone during aging. We report that a subset of neutrophils (TGFβ1+CCR5+) is the major source of TGFβ1 in murine bone. Their numbers are increased in bone marrow (BM) of aged wild-type mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CCL5, suggesting that TRAF3 in MPCs limits TGFβ1+CCR5+ neutrophil numbers in BM of young mice. During aging, TGFβ1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CCL5 by MPCs, associated with higher TGFβ1+CCR5+ neutrophil numbers in BM where they induce bone loss. TGFβ1+CCR5+ neutrophils decreased bone mass in male mice. The FDA-approved CCR5 antagonist, maraviroc, reduced TGFβ1+CCR5+ neutrophil numbers in BM and increased bone mass in aged mice. 15-mon-old mice with TGFβRII specifically deleted in MPCs had lower numbers of TGFβ1+CCR5+ neutrophils in BM and higher bone volume than wild-type littermates. We propose that pharmacologic reduction of TGFβ1+CCR5+ neutrophil numbers in BM could treat or prevent age-related osteoporosis.

 

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The passage describes a study investigating the mechanisms by which TGFβ1 induces age-related bone loss and suggests a potential treatment for osteoporosis based on the findings. The study reports that TGFβ1 promotes degradation of TRAF3, which is associated with decreased bone levels in mice and humans during aging. A subset of neutrophils (TGFβ1+CCR5+) is identified as the major source of TGFβ1 in murine bone, and their numbers are found to increase in bone marrow of aged mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs). This suggests that TRAF3 in MPCs limits TGFβ1+CCR5+ neutrophil numbers in the bone marrow of young mice.

During aging, TGFβ1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CCL5 by MPCs, associated with higher TGFβ1+CCR5+ neutrophil numbers in the bone marrow where they induce bone loss. TGFβ1+CCR5+ neutrophils are found to decrease bone mass in male mice. The FDA-approved CCR5 antagonist, maraviroc, is shown to reduce TGFβ1+CCR5+ neutrophil numbers in the bone marrow and increase bone mass in aged mice. Additionally, mice with TGFβRII specifically deleted in MPCs have lower numbers of TGFβ1+CCR5+ neutrophils in the bone marrow and higher bone volume than wild-type littermates.

Based on these findings, the study proposes that reducing TGFβ1+CCR5+ neutrophil numbers in the bone marrow could treat or prevent age-related osteoporosis. The use of maraviroc, a CCR5 antagonist, is suggested as a potential pharmacologic intervention for this purpose.

Related Products

Cat.No. Product Name Information
S2003 Maraviroc Maraviroc is a CCR5 antagonist for MIP-1α, MIP-1β and RANTES with IC50 of 3.3 nM, 7.2 nM and 5.2 nM in cell-free assays, respectively. Maraviroc is used in the treatment of HIV infection.

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