Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy

Abstract

Aging of the global population increases the incidence of osteoporosis and associated fragility fractures, significantly impacting patient quality of life and healthcare costs. The acute inflammatory reaction is essential to initiate healing after injury. However, aging is associated with “inflammaging”, referring to the presence of systemic low-level chronic inflammation. Chronic inflammation impairs the initiation of bone regeneration in elderly patients. This review examines current knowledge of the bone regeneration process and potential immunomodulatory therapies to facilitate bone healing in inflammaging.Aged macrophages show increased sensitivity and responsiveness to inflammatory signals. While M1 macrophages are activated during the acute inflammatory response, proper resolution of the inflammatory phase involves repolarizing pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype associated with tissue regeneration. In aging, persistent chronic inflammation resulting from the failure of M1 to M2 repolarization leads to increased osteoclast activation and decreased osteoblast formation, thus increasing bone resorption and decreasing bone formation during healing.Inflammaging can impair the ability of stem cells to support bone regeneration and contributes to the decline in bone mass and strength that occurs with aging. Therefore, modulating inflammaging is a promising approach for improving bone health in the aging population. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may benefit bone regeneration in inflammation. Preconditioning MSCs with pro-inflammatory cytokines affects MSCs’ secretory profile and osteogenic ability. MSCs cultured under hypoxic conditions show increased proliferation rates and secretion of growth factors. Resolution of inflammation via local delivery of anti-inflammatory cytokines is also a potential therapy for bone regeneration in inflammaging. Scaffolds containing anti-inflammatory cytokines, unaltered MSCs, and genetically modified MSCs can also have therapeutic potential. MSC exosomes can increase the migration of MSCs to the fracture site and enhance osteogenic differentiation and angiogenesis.In conclusion, inflammaging can impair the proper initiation of bone regeneration in the elderly. Modulating inflammaging is a promising approach for improving compromised bone healing in the aging population.

Recent trends in bone tissue engineering: a review of materials, methods, and structures

“…hMSCs are multipotent adult stem cells that hold great promise in restoring both the structure and function of damaged bone. MSCs have been shown to accelerate bone regeneration by enhancing angiogenesis, secreting growth factors and anti-inflammatory cytokines, and coordinating bone remodeling by differentiating into bone-forming cells [16,17]. In the processes of bone healing, a significant number of the cytokines such as G-CSF and SDF-1, growth factors such as VEGF-A and bFGF stimulate and reinforce endogenous MSC homing to damaged tissues [18].…”

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

“…Immune cytokines that play an essential role in bone regeneration include TNF-α, IL-1, IL-6, IL-17, and IFN-γ, as well as numerous other cytokines (e.g., IL-12, IL-23, IL-27, IL-35) [ 30 , 33 , 36 ]. More specifically, the immune-related cytokines IL-1β, ΙL-6, IL-17, and TNF-α are thought to be the primary inducers of osteoclastogenesis by enhancing the expression of factors involved in osteoclast differentiation, such as RANKL and the macrophage-colony-stimulating factor (M-CSF), favoring bone resorption [ 33 , 37 ]. Another class of inflammatory molecules promoting osteoclastogenesis is that of the chemokines, involving several C-C motif chemokine ligands (CCLs) (e.g., CCL3, CCL5, CCL9, etc.…”

Micropillars in Biomechanics: Role in Guiding Mesenchymal Stem Cells Differentiation and Bone Regeneration

“…Specific chemical stimuli can direct MSCs to differentiate into various cell types, including osteoblasts, adipocytes, neurons, or endothelial cells, contributing to osteogenesis, adipogenesis, neurogenesis, or angiogenesis, respectively. [56][57][58][59][60]…”