Bone regeneration and fracture repair mechanisms are compromised as people age. One mechanism to account for this decline is that skeletal stem and progenitor cells (SSPCs) are more prone to differentiate into fat-producing adipocytes than into bone-producing osteoblasts. New research indicates that this switch in SSPC differentiation occurs as a result of chronic inflammation that develops as we age.

X-ray image of right shoulder with proximal humerus fracture after operative fixation. Image courtesy of P. Leucht, New York University School of Medicine, USA.

“In the elderly, an imbalance between adaptive and innate immunity, as well as a progressive accumulation of senescent cells, lead to elevated levels of pro-inflammatory mediators, a process known as ‘inflamm-ageing’,” says Philipp Leucht, corresponding author of the new research.

Leucht and his team took bone samples from patients undergoing fracture fixation surgery (see image) and found an association between low SSPC number and a slow time to fracture union. This finding was replicated in a mouse tibial monocortical defect model, with better bone regeneration and a greater number of SSPCs in young (12 weeks) mice than in middle-aged (52 weeks) mice.

To distinguish chronological ageing from inflamm-ageing, the researchers showed that young Nfkb1–/– mice, which have constitutively active NFκB signalling and are a model of modest chronic inflammation, also have a low number of SSPCs. Furthermore, SSPCs from these mice display a senescent phenotype, an increased ability to differentiate into adipocytes and a reduced capacity for chondrogenic and osteogenic differentiation.

The researchers showed that treating middle-aged (52 weeks) mice with NSAIDs resulted in an increase in the number of SSPCs, and the transcriptional signature and function of these cells became more osteogenic, resembling SSPCs from young mice.

“Anti-inflammatory drugs could be taken prior to elective orthopedic surgery to improve stem cell number and function,” hypothesizes Leucht “But further research should be to target the SSPCs, to ameliorate the effects of age-associated inflammation on this cell type without inhibiting inflammation that is necessary for successful bone regeneration.”