Although bone morphogenetic protein-2 (BMP2) has demonstrated extraordinary potential in bone formation, its clinical applications require supraphysiological milligram-level doses that increase postoperative inflammation and inappropriate adipogenesis, resulting in well-documented life-threatening cervical swelling and cyst-like bone formation. Recent promising alternative biomolecular strategies are toward promoting pro-osteogenic activity of BMP2 while simultaneously suppressing its adverse effects. Here, we demonstrated that small molecular phenamil synergized osteogenesis and bone formation with BMP2 in a rat critical size mandibular defect model. Moreover, we successfully elicited the BMP2 adverse outcomes (i.e. adipogenesis and inflammation) in the mandibular defect by applying high dose BMP2. Phenamil treatment significantly improves the quality of newly formed bone by inhibiting BMP2 induced fatty cyst-like structure and inflammatory soft-tissue swelling. The observed positive phenamil effects were associated with upregulation of tribbles homolog 3 (Trib3) that suppressed adipogenic differentiation and inflammatory responses by negatively regulating PPARγ and NF-κB transcriptional activities. Thus, use of BMP2 along with phenamil stimulation or Trib3 augmentation may be a promising strategy to improve clinical efficacy and safety of current BMP therapeutics.

A 53-year-old woman with no past medical history presented to the Emergency Department with right frontal headache and ipsilateral neck pain. She was found to have right internal jugular vein thrombosis, right cerebellar stroke, meningitis, septic pulmonary emboli, and fusobacterium bacteremia, all consistent with a severe presentation of Lemierre’s syndrome (LS). While LS is often preceded by nasopharyngeal infection, no such history was elicited from our patient. Instead, concomitant papillary thyroid cancer with extension to her right internal jugular vein was implicated. Prompt recognition of these multiple related processes led to a timely initiation of appropriate therapy for infection, stroke, and malignancy.