title: Systemic regulation of angiogenesis and matrix degradation in bone regeneration--distraction osteogenesis compared to rigid fracture healing.
abstract: Aim of this study was the investigation of systemic biochemical regulation mechanisms of bone regeneration by angiogenic and matrix-degrading enzymes during distraction osteogenesis compared to rigid osteotomy bone healing. Serum samples of 10 otherwise healthy patients with callus distraction for lower limb-lengthening and 10 osteotomy patients undergoing elective axis correction have been collected prospectively in a standardized time schedule before and up to 6 months after the procedure. At the end of the individual investigation period, concentrations of metalloproteinases (MMP-9, -13), tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) and the angiogenic factors angiogenin and VEGF have been detected by use of commercially available enzyme immunoassays. Results have been compared to our preliminary study on proMMP-1-3. In distraction osteogenesis, significantly elevated serum concentrations compared to baseline could be detected postoperatively for proMMP-1, MMP-9, TIMP-1, angiogenin and VEGF but not for proMMP-2, proMMP-3 or TIMP-2. In patients with rigid osteotomy healing, MMP-9, TIMP-1, TIMP-2, angiogenin and VEGF were significantly increased respectively. Comparison of both patient collectives revealed significantly higher increases of serum proMMP-1, VEGF and TIMP-1 in distraction patients during the lengthening period and significantly higher serum concentrations of TIMP-2 in late fracture healing period in osteotomy patients. Serum levels of MMP-13 were below the lowest standards, and therefore quantitative analysis was not possible. Bone regeneration in distraction osteogenesis and rigid osteotomy healing is accompanied by systemic increase of matrix-degrading and angiogenic factors in a certain time course and quantity. This might reflect biochemical regulation of local bone healing in the circulation. ProMMP-1, VEGF and TIMP-1 seem to be key regulatory factors during distraction osteogenesis.
authors.affiliation: Orthopaedic University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. stefan.weiss@ok.uni-heidelberg.de
authors.forename: S
authors.initials: S
authors.lastname: Weiss
authors.forename: G
authors.initials: G
authors.lastname: Zimmermann
authors.forename: R
authors.initials: R
authors.lastname: Baumgart
authors.forename: P
authors.initials: P
authors.lastname: Kasten
authors.forename: M
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: P
authors.initials: P
authors.lastname: Henle
mesh_terms: D000328:Adult; D000368:Aged; D042501:Angiogenic Proteins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D050281:Bones of Lower Extremity / Q000293:injuries / Q000378:metabolism; D002146:Bony Callus / Q000378:metabolism / Q000601:surgery; D017364:Collagenases / Q000097:blood; D005260:Female; D017102:Fracture Healing; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000502:physiology; D019857:Osteogenesis, Distraction; D010027:Osteotomy; D012259:Ribonuclease, Pancreatic / Q000097:blood; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042501:Angiogenic Proteins; D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9