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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., (© 2023. The Author(s).)

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. Age-related osteoporosis is known to be dependent on TGFβ1 signalling. Here the authors show that a subset of neutrophils (identified by TGFβ1+CCR5+) increase during aging in mouse bone marrow resulting in bone loss, while a CCR5 antagonist can reduce the neutrophil numbers and increase bone mass in aged mice. [ABSTRACT FROM AUTHOR]