Royal College of Surgeons in Ireland
Staphylococcus induced bone loss and destruction in osteomyelitis.pdf (12.39 MB)

Staphylococcus induced bone loss and destruction in osteomyelitis

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posted on 2019-11-22, 17:49 authored by Amro Widaa

Osteomyelitis and Septic arthritis are infections of the bone or joint / subchondral bone respectively, which results in significant patient morbidity and mortality. The incidence of osteomyelitis is as high as 1 in every 5,000, with the most causative microorganisms to induce these infections being Staphylococcus aureus and Staphylococcus epidermidis, respectively. S. aureus and S. epidermidis are two gram positive bacteria that are found to colonise humans in high frequency as part of the normal bacterial flora. They are termed ‘opportunistic pathogens’ because when they gain access to typically sterile areas in the body they can cause infection. Osteomyelitis and Septic arthritis cause severe irreversible bone loss and destruction, and treatment of these infections are reliant on antibiotics. Unfortunately due to antibiotic resistant staphylococcal strains this treatment has become increasing unsuccessful and therefore elaborating the pathogenic mechanisms has become imperative. Currently the infectious mechanism(s) by which Staphylococci colonise, infect and induce bone loss / destruction is poorly understood. This research thesis identifies that Staphylococcal cell wall proteins mediate attachment to osteoblasts, resulting in multiple signals that may account for bone loss and destruction in patients. Understanding the molecular mechanism of Staphylococcal induced bone infections may help aid in the development of better and new treatments, rather than our over reliance of antibiotics that we have in our hospitals today.

We describe for the first time the virulence of S. aureus SpA, expressed in > 90% of S. aureus strains, in binding to osteoblasts and inducing multiple signals for bone loss and destruction. We have identified that S. aureus SpA binds to highly expressed Tumour necrosis factor receptor 1 (TNFR1) on osteoblasts, contributing to ~ 50% of the overall binding interaction. S. aureus SpA mimics TNF-a in binding TNFR1, and upon doing so activates downstream signalling of NFkB transcription. NFkB results in adverse effects on osteoblast, in terms of bone formation and resorption. S. aureus SpA induced apoptosis (Caspase 3 and Annexin V), inhibited osteoblast proliferation and osteogenic marker expression (alkaline phosphatase, osteopontin and subsequent mineralisation). Furthermore S. aureus SpA led to a bone resorptive state by the induction of RANKL and inhibition of OPG signalling from infected osteoblast, resulting in preosteoclast migration towards infected cells and consequent initiation of osteoclastogenesis. These adverse events were not observed when using S. aureus isogenic mutant strain defective in SpA or TNFR1 silenced osteoblast, while over expressing SpA in an isogenic mutant of S. aureus led to an increase of these adverse effects on bone formation and resorption.

Moreover we have identified S. epidermidis SdrG, expressed in > 90% of S. epidermidis strains, facilitates binding to an unknown osteoblast integrin. This binding interaction was strong in the presence of fibrinogen but not abolished in the absence of it, and may suggests that SdrG utilises a fibrinogen bridge to bind to an osteoblast integrin which may bind also to fibrinogen. SdrG effected osteoblast proliferation by inhibition and removal of SdrG did not completely recover osteoblast growth, and is indicative of a secondary binding interaction. Moreover S. epidermidis binding additionally induced osteoblast cell death independently of SdrG, raising an emphasis to elucidate on the other binding mechanism(s) of S. epidermidis to osteoblasts to induce bone infections.


First Supervisor

Dr Steven W. Kerrigan

Second Supervisor

Professor Fergal J. O'Brien


Submitted for the Award of Doctor of Philosophy (PhD) to the Royal College of Surgeons in Ireland, 2012.

Published Citation

Widaa, A. Staphylococcus induced bone loss and destruction in osteomyelitis. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2012.

Degree Name

  • Doctor of Philosophy (PhD)

Date of award


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