Action of IL‐1β during fracture healing

Abstract

After bone injury, developmental processes such as endochondral and intramembranous ossification are recapitulated as the skeleton regenerates. In contrast to development, skeletal healing involves inflammation. During the early stages of healing a variety of inflammatory cells infiltrate the injured site, debride the wound, and stimulate the repair process. Little is known about the inflammatory process during bone repair. In this work, we examined the effect of a pro-inflammatory cytokine, Interleukin-1 beta (IL-1b), on osteoblast and stem cell differentiation and on intramembranous and endochondral ossification, because IL-1b exerts effects on skeletal homeostasis and is upregulated in response to fracture. We determined that IL-1b stimulated proliferation of osteoblasts and production of mineralized bone matrix, but suppressed proliferation and inhibited differentiation of bone marrow derived MSCs. We next performed loss-and gain-offunction experiments to determine if altering IL-1b signaling affects fracture healing. We did not detect any differences in callus, cartilage, and bone matrix production during healing of nonstabilized or stabilized fractures in mice that lacked the IL-1b receptor compared to wildtype animals. We observed subtle alterations in the healing process after administering IL-1b during the early phases of repair. At day 10 after injury, the ratio of cartilage to callus was increased, and by day 14, the proportion of cartilage to total callus and to bone was reduced. These changes could reflect a slight acceleration of endochondral ossification, or direct effects on cartilage and bone formation.

Platelet-functionalized three-dimensional poly-ε-caprolactone fibrous scaffold prepared using centrifugal spinning for delivery of growth factors

“…Platelets play a pivotal role in these early phases of healing. IL-1 19 and IL-6 20 as pro-inflammatory cytokines play a role in macrophage activation. IL-17 was shown to be one of the key regulators in the early phases of bone healing via osteoblast maturation.…”

“…In biomaterials research, TNF-α and IL-1 are the best known mediators of the foreign body reaction. Lange et al 19 observed the positive effect of IL-1β on the proliferation of osteoblasts and the negative effect on the proliferation and differentiation of MSCs. Similarly, TNF-α was shown to inhibit the progress of bone healing by inducing osteoblast and chondrocyte apoptosis.…”

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

“…Unlike TNF-a, which does not affect skeletal development but is required for normal bone regeneration, absence of IL-1 does not affect in vivo fracture healing. 91 However, mice lacking IL-1a and/or IL-1b, the two forms of IL-1, have significantly higher bone mineral density and femoral bone mass than normal mice, which has been attributed to impaired osteoclast development. 92 In vitro studies of the effects of IL-1a and IL-1b on osteogenically differentiating MSCs have shown that these cytokines have similar effects as TNF-a.…”

Superior Potential of CD34-Positive Cells Compared to Total Mononuclear Cells for Healing of Nonunion following Bone Fracture

“…In the current study, the influences of cell-cell interaction arising from the difference in transplanted cell numbers between the two groups was not considered, which should be regarded as a limitation. It is well known that inflammatory signals play an important role in regulating fracture healing (42,49). In the early stages of fracture healing, the mRNA expression levels of inflammatory cytokines, including TNF-a, IL-1, and IL-6, are significantly elevated within the first few days after injuries at the perifracture sites (9,19,37,52).…”