Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features

• Published in: Journal of translational medicine Vol. 8; no. 1; p. 96
• Main Authors: Wehrhan, Falk, Hyckel, Peter, Ries, Jutta, Stockmann, Phillip, Nkenke, Emeka, Schlegel, Karl A, Neukam, Friedrich W, Amann, Kerstin
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.10.2010; BioMed Central; BMC
• Subjects: Bone Morphogenetic Proteins - genetics; Bones; Colleges & universities; Complications and side effects; Dilution; Diphosphonates; Diphosphonates - adverse effects; Gene expression; Glyceraldehyde-3-Phosphate Dehydrogenases - genetics; Humans; Immunohistochemistry; Jaw Diseases - chemically induced; Jaw Diseases - metabolism; Medical research; MSX1 Transcription Factor - genetics; MSX1 Transcription Factor - metabolism; Necrosis; Osteonecrosis - chemically induced; Osteonecrosis - metabolism; RANK Ligand - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Surgery; Germany
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/1479-5876-8-96

Bone-destructive disease treatments include bisphosphonates and antibodies against the osteoclast differentiator, RANKL (aRANKL); however, osteonecrosis of the jaw (ONJ) is a frequent side-effect. Current models fail to explain the restriction of bisphosphonate (BP)-related and denosumab (anti-RANKL antibody)-related ONJ to jaws. Msx-1 is exclusively expressed in craniofacial structures and pivotal to cranial neural crest (CNC)-derived periodontal tissue remodeling. We hypothesised that Msx-1 expression might be impaired in bisphosphonate-related ONJ. The study aim was to elucidate Msx-1 and RANKL-associated signal transduction (BMP-2/4, RANKL) in ONJ-altered and healthy periodontal tissue. Twenty ONJ and twenty non-BP exposed periodontal samples were processed for RT-PCR and immunohistochemistry. An automated staining-based alkaline phosphatase-anti-alkaline phosphatase method was used to measure the stained cells:total cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed on ONJ-affected and healthy jaw periodontal samples (n = 20 each) to quantitatively compare Msx-1, BMP-2, RANKL, and GAPDH mRNA levels. Semi-quantitative assessment of the ratio of stained cells showed decreased Msx-1 and RANKL and increased BMP-2/4 (all p < 0.05) expression in ONJ-adjacent periodontal tissue. ONJ tissue also exhibited decreased relative gene expression for Msx-1 (p < 0.03) and RANKL (p < 0.03) and increased BMP-2/4 expression (p < 0.02) compared to control. These results explain the sclerotic and osteopetrotic changes of periodontal tissue following BP application and substantiate clinical findings of BP-related impaired remodeling specific to periodontal tissue. RANKL suppression substantiated the clinical finding of impaired bone remodelling in BP- and aRANKL-induced ONJ-affected bone structures. Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling. Further research on developmental biology-related unique features of jaw bone structures will help to elucidate pathologies restricted to maxillofacial tissue.