Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice

Abstract

The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice.

Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism

“…Mice (aged ~12 weeks) were irradiated (900 cGy) and the tail vein injected with bone marrow isolated from age-matched donors (1 × 10 6 cells in 200 ml PBS). Engraftment into the bone marrow was allowed to occur for 2 months and verified using flow cytometry as previously described 36 .…”

Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels

“…Data available in the literature indicate multiple functions for macrophages during bone regeneration. Recently, the supportive function of F4/80 + macrophages during bone regeneration via enhanced osteogenesis when transplanted to aged individuals was demonstrated (46). In addition, it is known that F4/80 + osteomacs support osteoblast function (47).…”

Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches

“…Its role in influencing the differentiation of mesenchymal stem cells is still unclear [ 97 ]. Besides, the low-density lipoprotein receptor-related protein 1 (Lrp1) produced by young macrophage plays a role in bone homoeostasis, osteoblast function and even rejuvenate fracture repair in old mice [ 98 ]. Fu and co-workers reported that CCL3 inhibited osteoblast function and suppressed proliferation and osteogenic potential of osteoblasts in patients with myeloma bone disease.…”