Osteoimmunology: The effect of autoimmunity on fracture healing and skeletal analysis

Abstract

Understanding factors that affect bone response to trauma is integral to forensic skeletal analysis. It is essential in forensic anthropology to identify if impaired fracture healing impacts assessment of post-traumatic time intervals and whether a correction factor is required. This paper presents a synthetic review of the intersection of the literature on the immune system, bone biology, and osteoimmunological research to present a novel model of interactions that may affect fracture healing under autoimmune conditions. Results suggest that autoimmunity likely impacts fracture healing, the pathogenesis however, is under researched, but likely multifactorial. With autoimmune diseases being relatively common, significant clinical history should be incorporated when assessing skeletal remains. Future research includes the true natural healing rate of bone; effect of autoimmunity on this rate; variation of healing with different autoimmune diseases; and if necessary, development of a correction factor on the natural healing rate to account for impairment in autoimmunity.

Keywords: Autoimmunity; Forensic anthropology; Fracture healing; Osteoimmunology; Post-traumatic time interval; Rheumatoid arthritis.

Fig. 1

Innate immune response overview. Image adapted from Keogan et al. ([26], p.10).

Fig. 2

Adaptive immune response overview showing branches of the humoral (left) and cell-mediated (right) responses. Figure shows interaction between the two, represented by where the peripheral tolerance mechanism of Th cell co-stimulates the B cells for antibody release (see dotted arrows from cell-mediated immunity to humoral immunity). Image adapted from Keogan et al. ([26], p.11).

Fig. 3

Figure showing the factors influencing RANK/RANKL pathway activation and suppression by OPG. Image taken from Kenkre and Bassett ([72], p.315).

Fig. 4

Figure showing the effects of TNF-α in fracture healing. (1) Activates the release of RANKL, binding to RANK on osteoclasts, stimulating osteoclastogenesis, (2) depending on the phase of fracture healing, inhibits (early), or activates (later) osteoblasts to create new bone and secrete OPG, binding and inhibiting RANK on osteoclasts, (3) induces Dkk-1, a negative regulatory molecule of the Wnt pathway, inhibiting osteoblastogenesis [126]. Image adapted from Richardson et al. ([116], p.989).

Fig. 5

Th17 mediated mechanism of bone destruction in RA. RANKL/RANK pathway mediated bone resorption. Inflammatory cytokines activate Dkk-1, inhibiting bone formation. Image taken from Okamoto and Takayanagi ([9], p.14).

Fig. 6

Diagram showing the hypothetical mechanisms of osteoclastogenesis. Inhibitory IFN-γ was found to show a net increase in osteoclastogenesis. Hypothetically, one IFN-γ molecule stimulates a T cell to release one of each IFN-γ, TNF-α, RANKL, and further proinflammatory cytokines. This results in ∼75% of the released molecules (TNF-α, RANKL, and IL-1/IL-17) activating osteoclastogenesis, and 25% inhibiting (IFN-γ). Diagram by Author.

Fig. 7

Proposed graph for investigating the relationship between natural and autoimmune fracture healing rates. * Represent an example of the error bars that would show the 95% confidence interval at 50% observed healing. These would correspond to a time range (PTI) Image by Author.