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Expression of the Gene Encoding the Matrix Gla Protein by Mature Osteoblasts in Human Fracture Non-Unions

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Expression of the Gene Encoding the Matrix Gla Protein by Mature Osteoblasts in Human Fracture Non-Unions 92 J Clin Pathol: Mol Pathol 1999;52:92–96 Expression of the gene encoding the matrix gla protein by mature osteoblasts in human fracture Mol Path: first published as 10.1136/mp.52.2.92 on 1 April 1999. Downloaded from non-unions D M Lawton, J G Andrew, D R Marsh, J A Hoyland, A J Freemont Abstract used widely as a marker of bony tissue Background—Osteoblast phenotypic ab- development. Osteonectin, osteopontin (both normality, namely the expression of colla- functional members of the thrombospondin gen type III, has been shown previously in family), and osteocalcin appear to have roles in fracture non-union woven bone. mineralisation; in addition, osteopontin and Aims—To investigate osteoblasts from osteocalcin seem to have functions in fracture non-unions for evidence of gene resorption.12 During skeletogenesis, expres- expression of non-collagenous bone ma- sion of the gene encoding MGP (a protein trix proteins that have been implicated in originally described in bone matrix) has been mineralisation, namely matrix gla protein used as a reliable marker of the chondrogenic (MGP), osteonectin, osteopontin, and os- lineage,3–5 with osteoblasts appearing uniformly teocalcin. MGP is a consistent component negative. of bone matrix, but there are no reports of In the process of fracture healing, the osteoblasts in the skeleton expressing the evidence published to date on non-collagenous gene for MGP, and the site of synthesis of bone matrix proteins is solely from an animal skeletal MGP (perhaps the liver) has yet to model using the rat femur.6–8 Although this sys- be determined. tem has been used widely as a model of human Methods—Biopsies from normally heal- fracture healing, there are some diVerences: ing human fractures and non-unions were cartilage production in human fracture callus examined by means of in situ hybridisa- appears to be less exuberant, and the process of tion, using 35S labelled probes and autora- callus mineralisation appears to take place later diography to disclose levels of gene in humans than in the rat. The importance of expression. open epiphyses in the adult rat to chondrocyte Results—In normally healing fractures, behaviour in this model is unclear, but fracture mature osteoblasts on woven bone were repair in children (who have open epiphyses) http://mp.bmj.com/ negative for MGP mRNA, but positive for exhibits clear diVerences from the process in osteonectin, osteopontin, and osteocalcin adults. We studied the expression of the genes mRNA molecules. In non-unions, osteob- encoding MGP, osteonectin, osteopontin, and lasts displayed a novel phenotype: they osteocalcin to determine whether woven bone were positive for MGP mRNA, in addition development in normally healing human frac- to osteonectin, osteopontin, and osteocal- tures is similar to that described in the rat, and Department of cin mRNA molecules. whether diVerences existed in fracture non- on September 26, 2021 by guest. Protected copyright. Pathological Sciences, Conclusions—Mature osteoblasts in unions compared with normally healing bone. University of slowly healing fractures have an unusual Manchester, Stopford phenotype: they express the gene encoding Building, Oxford MGP,which indicates that control of osteo- Materials and methods Road, Manchester TISSUE PREPARATION M13 9PT, UK blast gene expression in non-unions is D M Lawton likely to be abnormal. This might be of Specimens of human fracture callus from nor- J A Hoyland importance in the pathogenesis of non- mally healing fractures were taken when avail- A J Freemont uniting human fractures, and is of current able from the fracture sites of 15 closed interest given the emerging status of MGP fractures during surgery carried out to treat Department of as an inhibitor of mineralisation. malreduction that had developed during con- Orthopaedic Surgery, ( 1999;52:92–96) servative treatment. Biopsies were obtained University of J Clin Pathol: Mol Pathol between one and four weeks after fracture. Manchester, Clinical Keywords: fracture non-union; osteoblast; woven bone; Sciences Building, in situ hybridisation; matrix gla protein; osteonectin; Patients were aged between 18 and 87 years Hope Hospital, Eccles osteopontin and were otherwise fit. On subsequent follow Old Road, Salford up, to one year, all these fractures, classed as M6 8HD, UK normally healing, were found to have united J G Andrew D R Marsh Several non-collagenous bone matrix proteins, normally. Abnormally healing fracture callus including matrix gla protein (MGP), from non-unions was taken from the fracture Correspondence to: osteonectin/SPARC, osteopontin (formerly site of 12 patients with extra-articular ununited Dr D M Lawton, SPP1), and osteocalcin (formerly BGP (bone fractures between four and 48 months after Department of Communication and gla protein)) are found in large quantities in fracture. Neuroscience, University of bone. They are thought to play a variety of The biopsy specimens were fixed in 10% Keele, Keele, StaVordshire important roles in bone development, growth, neutral buVered formalin, decalcified in 20% ST5 5BG, UK. and turnover and are also thought to be EDTA (pH 7.2) until decalcification was Accepted for publication involved in fracture repair. Osteocalcin appears radiologically complete, embedded in paraYn 17 November 1998 to be unique to bone and dentine, and has been wax, and sectioned at 7 µm. Osteoblasts express the MGP gene 93 IN SITU HYBRIDISATION (ISH) was obtained from Dr PJ Barr (Chiron Corpo- The probes used for ISH analysis of human ration, Emeryville, California, USA). Details of osteonectin, osteopontin, and MGP were these primers are as follows: osteonectin, clone Mol Path: first published as 10.1136/mp.52.2.92 on 1 April 1999. Downloaded from obtained from the American Type Culture HHCH67, restriction digest insert ECORI Collection (ATCC), and that for osteocalcin 1.2 kb910; osteopontin, clone Op-30, 1.4 kb11; http://mp.bmj.com/ on September 26, 2021 by guest. Protected copyright. Figure 1 In situ hybridisation (ISH) for matrix gla protein (MGP), osteonectin, osteopontin, and osteocalcin in human fracture callus; haematoxylin and eosin stained. Sections (A) and (B) are from a non-union fracture; sections (C–P) are from normally healing fractures. (A) MGP and (B) control (RNAase): osteoblasts on woven bone surfaces in non-unions were positive for MGP mRNA signal; test and control are from the same area of the same specimen block. Sections (C–G) ISH for osteonectin. (C) In early woven bone osteoblasts were strongly positive for osteonectin mRNA signal; the area selected in (D) shows the area indicated in C (arrow) at a higher magnification; (E) osteonectin and (F) control (RNAase) in early woven bone: non-cuboidal osteoblasts on the surface of woven bone, and many included osteoblasts, were positive for osteonectin mRNA signal; (G) osteonectin in woven bone: plump osteoblasts on the surface of woven bone were positive for osteonectin mRNA signal. Sections (H–N) ISH for osteopontin. (H) In early woven bone osteoblasts were weakly positive for osteopontin mRNA signal, in contrast to a strong osteonectin mRNA signal in the same area (C and D); the area selected in (I) shows the area indicated in H (arrow) at a higher magnification; (J) osteopontin and (K) control (RNAase) in woven bone: plump cuboidal osteoblasts on woven bone were positive for osteopontin mRNA signal, whereas included osteoblasts were negative; (L) osteopontin in lamellar bone: most flattened cells on the surface of lamellar bone were negative for osteopontin mRNA signal, but occasional, scattered cells (about 10% of the total) were positive (arrow); (M) osteopontin and (N) control (RNAase): multinucleate osteoclast-like cells were positive for osteopontin mRNA signal (arrow). Section (O) ISH for osteocalcin and (P) control (RNAase): multinucleate osteoclast-like cells were positive for osteocalcin mRNA signal, to our knowledge a new finding for this cell type. 94 Lawton, Andrew, Marsh, et al Table 1 Human: non-collagenous bone matrix protein gene expression in normally healing On microscopy, cells were categorised as fractures and non-unions chondrocytes, osteoblasts, and so on, in terms of their morphology and relation with their Mol Path: first published as 10.1136/mp.52.2.92 on 1 April 1999. Downloaded from MGP Osteonectin Osteopontin Osteocalcin extracellular matrix; that is, the presence of Haematoma lacunae, capsule/pericellular matrix, processes, Macrophages, − + + − Polymorphs − − − − and location on the surface of bone trabeculae. Granulation tissue mesenchyme − + + + Woven bone osteoblasts − + Early +/− + + Only in Later + Results non-unions Human fracture callus has a heterogeneous Lamellar bone flat lining cells − +/− +10%, scattered +/− appearance at histological examination, with individuals Multinucleate resorptive cells − − + + several of the elements of normal fracture heal- Endothelial cells − − − − ing being present in close proximity in any one section. These elements include haematoma, MGP, clone hmGLA-19, ECORI insert fibrous tissue, woven and compact lamellar 700 bp12; osteocalcin, clone hBGP-1, 455 bp, bone, and cartilage. Because of this heteroge- containing a 300 nucleotide (19–318) open neous appearance, callus specimens were reading frame encoding a 100 amino acid graded 1–3 according to the predominant human BGP precursor.13 appearance of the callus, and cellular events were related to the histological grade, as follows: grade 1, fracture blood clot (hae- PROBE PREPARATION AND HYBRIDISATION matoma)
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