title: Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions.
abstract: Bone morphogenetic proteins (BMPs) are increasingly being used clinically to enhance fracture repair and healing of non-unions. However, the potential efficacy of supraphysiological dosing for clinical results warrants further clarification of the BMP signaling pathway in human fracture healing. As BMP signaling can be fine-tuned at numerous levels, the role of BMP-inhibitors has become a major focus. The aim of the present study was to document co-expression of BMPs, pSmad 1/5/8, and BMP-inhibitors in human fracture callus and human non-unions. Using human tissue of fracture callus (n=14) and non-unions (n=4) we documented expression of BMPs (BMP2, BMP3 and BMP7), pSmad 1/5/8 and the BMP-inhibitors noggin, gremlin, chordin, Smad-6, Smad-7 and BAMBI. Co-expression of pSmad 1/5/8, BMPs and BMP-inhibitors was noted in the osteoblasts of fracture callus as well as of non-unions. Expression of BMP-inhibitors was generally stronger in non-unions than in fracture callus. The most pertinent differences were noted in the cartilaginous tissue components. Expression of BMP2 in chondrocytes was markedly decreased in non-unions compared to fracture callus and that of BMP7 was almost completely absent. Expression of BMP-inhibitors was almost the same in osteoblasts, chondrocytes and fibroblasts of fracture callus and well as in non-unions. Interestingly, although BMP ligands were present in the chondrocytes and fibroblasts of non-unions, they did not co-express pSmad 1/5/8 suggesting that BMP signaling may have been inhibited at some point before Smad 1/5/8 phosphorylation. These results suggest co-expression of BMP, pSmad 1/5/8 and BMP-inhibitors occurs in human fracture callus as well as non-unions but the relative expression of BMPs vs. BMP-inhibitors was different between these two tissue types. In contrast to our expectations, the expression of BMP inhibitors was comparable between fracture callus and non-unions, whereas the expression of BMPs was notably lower in the cartilaginous component of the non-unions in comparison to fracture callus. Based on these results, we believe that aberrations in the BMP-signaling pathway in the cartilaginous component of fracture healing could influence clinical fracture healing. An imbalance between the local presence of BMP and BMP-inhibitors may switch the direction towards healing or non-healing of a fracture.
authors.affiliation: Department of Orthopaedic Surgery, Academic Medical Centre, Amsterdam, The Netherlands. p.kloen@amc.uva.nl
authors.forename: Peter
authors.initials: P
authors.lastname: Kloen
authors.forename: Dominique
authors.initials: D
authors.lastname: Lauzier
authors.forename: Reggie C
authors.initials: RC
authors.lastname: Hamdy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055398:Bone Morphogenetic Protein 3 / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002146:Bony Callus / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D017102:Fracture Healing / Q000502:physiology; D050723:Fractures, Bone / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D051905:Smad6 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D055815:Young Adult; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D055398:Bone Morphogenetic Protein 3; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051905:Smad6 Protein; D051906:Smad7 Protein; D000099176:Noggin Protein; C485671:BAMBI protein, human; C486399:GREM1 protein, human; C054234:chordin