Toll-Like Receptor 2 Stimulation of Osteoblasts Mediates Staphylococcus Aureus Induced Bone Resorption and Osteoclastogenesis through Enhanced RANKL.

Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. We, therefore, investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption. S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kB ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. Bone resorption induced by S. aureus was abolished by OPG. S. aureus increased the expression of osteoclastogenic cytokines and prostaglandins in the parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. Our study indicates the importance of using different in vitro approaches for studies of how S. aureus regulates osteoclastogenesis to obtain better understanding of the complex mechanisms of S. aureus induced bone destruction in vivo.

Parietal bone osteomyelitis in melioidosis.

We report a case of a 55-year-old man with uncontrolled diabetes who presented with pneumonia. During his hospital stay his clinical status worsened and he had a focal seizure. MRI showed central nervous system involvement and parietal bone osteomyelitis. As the patient's blood culture and endotracheal aspirate grew Burkholderia pseudomallei, melioidosis was diagnosed. He was treated with meropenem after failure to respond to ceftazidime. He gradually improved over a period of 4 weeks and was discharged. Early diagnosis and therapy resulted in improved outcome.

Cranial melioidosis presenting as a mass lesion or osteomyelitis.

OBJECT: Melioidosis is caused by Burkholderia pseudomallei and causes multiple abscesses in different organs of the body. Cranial melioidosis, although uncommon, is sometimes confused with tuberculosis and is therefore under-recognized. The authors report on 6 cases of cranial infections caused by Burkholderia pseudomallei, presenting as mass lesions or cranial osteomyelitis, and review the literature. METHODS: The authors performed a retrospective review of the records of patients with cranial melioidosis treated at their institution between 1998 and 2005 to determine the presentation, management, and outcome of patients with this infection. RESULTS: Of the 6 patients diagnosed with cranial melioidosis during this period, 4 had brain abscesses and 2 had cranial osteomyelitis. All patients were treated surgically, and a diagnosis was made on the basis of histopathological studies. All patients were started on antibiotic therapy following surgery and this was continued for 6 months. One patient died soon after stereotactic aspiration of a brain abscess, and the other 5 patients had good outcomes. CONCLUSIONS: Cranial melioidosis is probably more prevalent than has been previously reported. A high index of suspicion, early diagnosis, initiation of appropriate antibiotic therapy and treatment for an adequate period are essential for assuring good outcome in patients with cranial melioidosis. The authors recommend surgery followed by intravenous ceftazidime treatment for 6 weeks and oral cotrimoxazole for 6 months thereafter in patients with cranial melioidosis.

Intracranial granuloma and skull osteolysis: complication of a primary cutaneous cryptococcosis in a kidney transplant recipient.

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. It occurs almost exclusively in the late posttransplantation period (>6 months after the initiation of immunosuppression). Subclinical onset of meningitis is the usual clinical presentation. Despite initiation of therapy, the mortality rate associated with this infection in this patient population remains high. To the best of our knowledge, this report describes one of the first cases of a rare entity: a primary cutaneous cryptococcosis in a renal transplant recipient disclosed by skull osteomyelitis and pseudotumoral intracranial extension. Surgical debridement and azole antifungal therapy were performed. Ten months after the onset of treatment, the patient feels good, clinical examination findings are normal, and no sign of evolutive cryptococcosis is noted.

In vivo induction of proinflammatory cytokines in mouse tissue by Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans.

Periodontitis is a chronic inflammatory disease initiated by a multitude of bacteria. Persistent infection leads to generation of various inflammatory mediators, resulting in tissue destruction and osteoclastic resorption of the alveolar bone. This study describes a novel in vivo murine calvarial model to assess the effects of oral pathogens on the expression of three proinflammatory cytokines [interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha] which are involved in bone resorption. We chose Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans as prototype oral pathogens. We also tested the effects of Streptococcus gordonii, an oral commensal supragingival microorganism, considered a non-pathogen. Live bacteria were injected into subcutaneous tissue overlying the parietal bone of mice calvaria for 6 days. At the end of the experimental period, tissues overlying the calvaria were removed and analyzed for proinflammatory cytokine expression by Northern blotting. Cytokine mRNA was not detected in the tissue over the calvaria of control animals. In contrast, P. gingivalis and A. actinomycetemcomitans elicited mRNA expression of all three cytokines, TNFalpha being the highest (TNFalpha > > IL-1beta > IL-6). P. gingivalis was more potent than A. actinomycetemcomitans in inducing cytokine expression. In contrast, S. gordonii induced only low levels of mRNA for IL-1beta and TNFalpha but no IL-6 mRNA induction. These results suggest that oral microorganisms with access to host tissues elicit a battery of proinflammatory cytokines. There were clear differences in profiles and, interestingly, a commensal bacterium also stimulated bone resorptive cytokine expression in host tissues.

Primarily infected cephalhematoma and osteomyelitis in a newborn.

Cephalhematomas are subperiosteal blood collections occurring in newborns secondary to trauma at birth. They develop within a few days and are subsequently resorbed. Infection of a cephalhematoma is unusual and caused most often by colonization of the hematoma during bacteremia or by direct inoculation secondary to trauma. Less than 10 patients with primary infection of the hematoma, in the absence of a positive blood culture, complicated by osteomyelitis have been described. We report a newborn with a primarily infected cephalhematoma complicated by parietal bone osteomyelitis.