Small molecule-mediated tribbles homolog 3 promotes bone formation induced by bone morphogenetic protein-2.
Jiabing FanJoan Pi-AnfrunsMian GuoDan C S ImZhong-Kai CuiSoyon KimBenjamin M WuTara L AghalooMin LeePublished in: Scientific reports (2017)
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.
Keyphrases
- mesenchymal stem cells
- bone regeneration
- oxidative stress
- small molecule
- signaling pathway
- soft tissue
- high dose
- gene expression
- bone marrow
- cell proliferation
- low dose
- patients undergoing
- risk assessment
- transcription factor
- immune response
- type diabetes
- poor prognosis
- toll like receptor
- lps induced
- metabolic syndrome
- drug induced
- anti inflammatory
- pi k akt
- single molecule
- bone mineral density