Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures

Center for Tissue Regeneration and Repair, Department of Orthopaedic Surgery, University of California, Davis, 4860 Y Street, Suite 3800, Sacramento, California 95817, USA.
Journal of Orthopaedic Research (Impact Factor: 2.97). 07/2006; 24(7):1463-71. DOI: 10.1002/jor.20182
Source: PubMed

ABSTRACT Nonunion is a challenging problem that may occur following certain bone fractures. However, there has been little investigation of the molecular basis of nonunions. Bone morphogenetic proteins (BMPs) play a significant role in osteogenesis. However, little is known about the expression patterns of BMPs in abnormal bone healing that results in nonunion formation. These facts prompted us to investigate and compare the gene expression patterns of BMPs and their antagonists in standard healing fractures and nonunions using rat experimental models. Standard closed healing fractures and experimental atrophic nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of standard healing fracture and fibrous tissue of nonunion (n=4 per each time point and each group). Gene expression of BMPs, BMP antagonists, and other regulatory molecules were studied by methods including Genechip microarray and real-time quantitative RT-PCR. Gene expression of BMP-2, 3, 3B, 4, 6, 7, GDF-5, 7, and BMP antagonists noggin, drm, screlostin, and BAMBI were significantly lower in nonunions compared to standard healing fractures at several time points. Downregulation in expression of osteogenic BMPs may account for the nonunions of fracture. The balance between BMPs and their endogenous antagonists is critical for optimal fracture healing.

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    • "Co-localization of BMP4 and noggin was the same in osteoblasts, chondrocytes and hypertrophic chondrocytes First to report noggin in animal model First to suggest that balance between noggin and BMP4 important for fracture healing Niikura–2006 [33] Rat femoral fracture Normal healing vs. atrophic non-union Microarray analysis of >31,000 genes Microarray, qRT-PCR Gene expression of BMP2, BMP3, BMP3B, BMP4, BMP6, BMP7, GDF5, GDF7 and noggin, drm, sclerostin and BAMBI was significantly lower in non-unions compared to healing fractures at several time points Concluded that down-regulation of BMP components may account for the non-unions of fractures Balance between BMPs and their antagonists is critical for fracture healing Yu–2010 [37] "
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    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.
    Bone 04/2012; 51(1):59-68. DOI:10.1016/j.bone.2012.03.032 · 4.46 Impact Factor
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    • "During the remodeling of cartilage into woven bone, BMP3, BMP4, BMP7 and BMP8 plus BMP2, BMP5 and BMP6 are upregulated (Ai-Aql et al. 2008), whereas the expression of most bone-healing-related factors is downregulated in non-unions (Niikura et al. 2006). BMP2 is essential for the initiation of fracture healing. "
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    ABSTRACT: The musculoskeletal system is a tight network of many tissues. Coordinated interplay at a biochemical level between tissues is essential for development and repair. Traumatic injury usually affects several tissues and represents a large challenge in clinical settings. The current demand for potent growth factors in such applications thus accompanies the keen interest in molecular mechanisms and orchestration of tissue formation. Of special interest are multitasking growth factors that act as signals in a variety of cell types, both in a paracrine and in an autocrine manner, thereby inducing cell differentiation and coordinating not only tissue assembly at specific sites but also maturation and homeostasis. We concentrate here on bone morphogenetic proteins (BMPs), which are important crosstalk mediators known for their irreplaceable roles in vertebrate development. The molecular crosstalk during embryonic musculoskeletal tissue formation is recapitulated in adult repair. BMPs act at different levels from the initiation to maturation of newly formed tissue. Interestingly, this is influenced by the spatiotemporal expression of different BMPs, their receptors and co-factors at the site of repair. Thus, the regenerative potential of BMPs needs to be evaluated in the context of highly connected tissues such as muscle and bone and might indeed be different in more poorly connected tissues such as cartilage. This highlights the need for an understanding of BMP signaling across tissues in order to eventually improve BMP regenerative potential in clinical applications. In this review, the distinct members of the BMP family and their individual contribution to musculoskeletal tissue repair are summarized by focusing on their paracrine and autocrine functions.
    Cell and Tissue Research 02/2012; 347(3):521-44. DOI:10.1007/s00441-011-1283-6 · 3.33 Impact Factor
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    • "Although the clinical risk factors for fracture nonunion are well known, the pathological processes and pathogenesis remain unclear . Recent studies demonstrated that the reduced bone forming activity in nonunion may attribute to the deficiency of key growth factors regulating normal fracture healing [33] [34] [35] "
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    ABSTRACT: The traumatic temporomandibular joint (TMJ) bony ankylosis has generated great interest in the cranio-maxillofacial surgeons yet remains an enigma, due to its unknown pathogenesis. Organization and ossification of hematoma is the classical hypothesis concerning the underlying pathophysiology, but it could not explain all the unique characters of TMJ bony ankylosis. The previous imaging descriptions about bony ankylosis tend to over-emphasize the obliteration of joint space and the overgrowth of new bone around the joint. Our recent study has found that the radiolucent zone in the bony fusion area indicating impaired bone healing is one of the most important imaging features of bony ankylosis, and this imaging feature is similar to that of hypertrophic nonunion of long bone. We also observe that there is close relationship between the mouth opening and the degree of calcification of radiolucent zone. Therefore, we hypothesize that the development of traumatic TMJ bony ankylosis may be the course of bone healing of two injured articular surfaces under the interference of opening movement, which is similar to the hypertrophic nonunion. Our hypothesis could help to explain some unintelligible characters of bony ankylosis, and deserves further studies.
    Medical Hypotheses 11/2011; 78(2):273-6. DOI:10.1016/j.mehy.2011.10.044 · 1.07 Impact Factor
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