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Unveiling the Bmp13 Enigma: Redundant Morphogen or Crucial Regulator?
Lisa A Williams, Divya Bhargav, Ashish D Diwan
International Journal of Biological Sciences , 2008,
Abstract: Bone morphogenetic proteins are a diverse group of morphogens with influences not only on bone tissue, as the nomenclature suggests, but on multiple tissues in the body and often at crucial and influential periods in development. The purpose of this review is to identify and discuss current knowledge of one vertebrate BMP, Bone Morphogenetic Protein 13 (BMP13), from a variety of research fields, in order to clarify BMP13's functional contribution to developing and maintaining healthy tissues, and to identify potential future research directions for this intriguing morphogen. BMP13 is highly evolutionarily conserved (active domain >95%) across diverse species from Zebrafish to humans, suggesting a crucial function. In addition, mutations in BMP13 have recently been associated with Klippel-Feil Syndrome, causative of numerous skeletal and developmental defects including spinal disc fusion. The specific nature of BMP13's crucial function is, however, not yet known. The literature for BMP13 is focused largely on its activity in the healing of tendon-like tissues, or in comparisons with other BMP family molecules for whom a clear function in embryo development or osteogenic differentiation has been identified. There is a paucity of detailed information regarding BMP13 protein activity, structure or protein processing. Whilst some activity in the stimulation of osteogenic or cartilaginous gene expression has been reported, and BMP13 expression is found in post natal cartilage and tendon tissues, there appears to be a redundancy of function in the BMP family, with several members capable of stimulating similar tissue responses. This review aims to summarise the known or potential role(s) for BMP13 in a variety of biological systems.
Genetic Analysis of the Roles of BMP2, BMP4, and BMP7 in Limb Patterning and Skeletogenesis  [PDF]
Amitabha Bandyopadhyay equal contributor,Kunikazu Tsuji equal contributor,Karen Cox,Brian D Harfe,Vicki Rosen,Clifford J Tabin
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020216
Abstract: Bone morphogenetic protein (BMP) family members, including BMP2, BMP4, and BMP7, are expressed throughout limb development. BMPs have been implicated in early limb patterning as well as in the process of skeletogenesis. However, due to complications associated with early embryonic lethality, particularly for Bmp2 and Bmp4, and with functional redundancy among BMP molecules, it has been difficult to decipher the specific roles of these BMP molecules during different stages of limb development. To circumvent these issues, we have constructed a series of mouse strains lacking one or more of these BMPs, using conditional alleles in the case of Bmp2 and Bmp4 to remove them specifically from the limb bud mesenchyme. Contrary to earlier suggestions, our results indicate that BMPs neither act as secondary signals downstream of Sonic Hedghog (SHH) in patterning the anteroposterior axis nor as signals from the interdigital mesenchyme in specifying digit identity. We do find that a threshold level of BMP signaling is required for the onset of chondrogenesis, and hence some chondrogenic condensations fail to form in limbs deficient in both BMP2 and BMP4. However, in the condensations that do form, subsequent chondrogenic differentiation proceeds normally even in the absence of BMP2 and BMP7 or BMP2 and BMP4. In contrast, we find that the loss of both BMP2 and BMP4 results in a severe impairment of osteogenesis.
Shaping Skeletal Growth by Modular Regulatory Elements in the Bmp5 Gene  [PDF]
Catherine Guenther equal contributor,Luiz Pantalena-Filho equal contributor,David M. Kingsley
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000308
Abstract: Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body.
The BMP Antagonist Follistatin-Like 1 Is Required for Skeletal and Lung Organogenesis  [PDF]
Marc Sylva, Vivian S. W. Li, Anita A. A. Buffing, Johan H. van Es, Maaike van den Born, Saskia van der Velden, Quinn Gunst, Jan Harm Koolstra, Antoon F. M. Moorman, Hans Clevers, Maurice J. B. van den Hoff
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022616
Abstract: Follistatin-like 1 (Fstl1) is a secreted protein of the BMP inhibitor class. During development, expression of Fstl1 is already found in cleavage stage embryos and becomes gradually restricted to mesenchymal elements of most organs during subsequent development. Knock down experiments in chicken and zebrafish demonstrated a role as a BMP antagonist in early development. To investigate the role of Fstl1 during mouse development, a conditional Fstl1 KO allele as well as a Fstl1-GFP reporter mouse were created. KO mice die at birth from respiratory distress and show multiple defects in lung development. Also, skeletal development is affected. Endochondral bone development, limb patterning as well as patterning of the axial skeleton are perturbed in the absence of Fstl1. Taken together, these observations show that Fstl1 is a crucial regulator in BMP signalling during mouse development.
New Insights into the Structural Roles of Nebulin in Skeletal Muscle
Coen A. C. Ottenheijm,Henk Granzier
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/968139
Abstract: One important feature of muscle structure and function that has remained relatively obscure is the mechanism that regulates thin filament length. Filament length is an important aspect of muscle function as force production is proportional to the amount of overlap between thick and thin filaments. Recent advances, due in part to the generation of nebulin KO models, reveal that nebulin plays an important role in the regulation of thin filament length. Another structural feature of skeletal muscle that is not well understood is the mechanism involved in maintaining the regular lateral alignment of adjacent sarcomeres, that is, myofibrillar connectivity. Recent studies indicate that nebulin is part of a protein complex that mechanically links adjacent myofibrils. Thus, novel structural roles of nebulin in skeletal muscle involve the regulation of thin filament length and maintaining myofibrillar connectivity. When these functions of nebulin are absent, muscle weakness ensues, as is the case in patients with nemaline myopathy with mutations in nebulin. Here we review these new insights in the role of nebulin in skeletal muscle structure.
STERNUM MALFORMATIONS AS A RESULT OF BMP4 DEFICIENCY  [cached]
A Radulescu
Jurnalul Pediatrului , 2005,
Abstract: Recent data shows that the Bmp4 plays significant roles in a large number of developmental processes,including branching morphogenesis of the lung, toothdevelopment, lens development, neuroepithelial cell diferentiation, primordial germ cell formation, and not leats most importantly bone formation and development.The purpose of this study was to identify the Bmp4 expression and its role in the development of ribs and sternum and analysis of the skeletal phenotypes caused by the genetic inactivation of Bmp4. along with the study of it’s expression patterns.This conclusion of this study is based in part on the finding that some heterozygous mutants, which presumably produce half the amount of active BMP protein as wild type appear to have some skeletal defects with regards to the sternum and ribs.
Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation
Andrew M Ho, Paul C Marker, Hairong Peng, Andres J Quintero, David M Kingsley, Johnny Huard
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-35
Abstract: Here, we identify a novel germline mutation at the mouse Bone morphogenetic protein 5 (Bmp5) locus. Genetic analysis shows that the mutation occurs at a site encoding the proteolytic processing sequence of the BMP5 protein and blocks proper processing of BMP5. Anatomic studies reveal that this mutation affects the formation of multiple skeletal features including several muscle-induced skeletal sites in vivo. Biomechanical studies of osteoblasts from these anatomic sites show that the mutation inhibits the proper response of bone cells to mechanical stimulation.The results from these genetic, biochemical, and biomechanical studies suggest that BMPs are required not only for skeletal patterning during embryonic development, but also for bone response and remodeling to mechanical stimulation at specific anatomic sites in the skeleton.An area of significant interest in orthopaedics and rehabilitation medicine is the effect of mechanical loading on bone formation and remodeling. Mechanical stimulation plays an important role in determining bone mass and density in the adult skeleton, as well as susceptibility to conditions such as fractures or osteoporosis. It has long been observed that bone mass and mineral density can be altered at very specific sites of the skeleton in response to mechanical stimulation during exercise, as seen in increased size and cortical thickness of the arm bone from the dominant side in tennis players [1-3] and the increased mineralization seen in the lumbar spine of weight lifters [4] or in the heel bone of runners [5]. In general, increased exercise or muscular loading will increase bone mass [6,7] or bone density [8,9]. In contrast, decreased loading will reduce osteogenic activity, as seen in the bones of test animals in space flight [10] or of patients in prolonged bed rest [11].Since Wolff's observation in 1892 that mechanical stress is a primary determinant in bone adaptation [12], extensive studies have been performed to understand how
Elucidation of the potential roles of matrix metalloproteinases in skeletal biology
Stephen M Krane
Arthritis Research & Therapy , 2002, DOI: 10.1186/ar600
Abstract: In a recent review in Arthritis Research, Murphy et al. emphasized the importance of degradative processes in joint tissue destruction in various forms of arthritis [1]. They presented aspects of the background biochemistry of the matrix metalloproteinases (MMPs) as 'major players' in the physiological turnover of the extracellular matrix and in the pathological destruction in disease. Specific inhibitors were introduced as potential therapy for arthritis, based on the potential roles of MMPs even though they were directed at downstream events.Despite phenomenal advances in this area, it is still necessary to establish the importance of MMPs in processes such as normal embryonic development and adult tissue remodeling. This is essential to targeting a specific gene product whose function is thought to be critical in pathological events (e.g. degradation of bone and soft tissue extracellular matrices), in disorders such as osteoarthritis and rheumatoid arthritis. There are several approaches to establish that a MMP has the postulated biological function in arthritis. It is not sufficient only to demonstrate the presence of the MMP in tissue extracts or by immunohistochemistry in tissue sections, or to find elevated levels of mRNA in extracted RNA by northern hybridization, by quantitative PCR or by in situ hybridization in tissue sections. The identification in affected tissues of the specific cleavage product of a MMP-catalyzed reaction provides better evidence for an in vivo function. For example, using antibodies directed against the collagenase cleavage site in collagens, positive staining has been found for cleavage products of type I collagen in bone and of type II collagen in cartilage [2,3]. The expected effect of a specific enzyme inhibitor drug supports the role of the enzyme, although in the case of MMP inhibitors the specificity in vivo is yet to be established [4]. The demonstration of the expected phenotype that results from a spontaneous mutation in a
Roles of BMP6/7 in Actin Dynamics in Amyloid β-Induced Neurotoxicity  [PDF]
Lin Sun, Yingjie Zhang, Shifu Xiao
Psychology (PSYCH) , 2014, DOI: 10.4236/psych.2014.57082
Abstract:

Actin dynamics plays an important role in many physiological functions such as long-term potentiation, neurotransmission, regulatory proteins translocation, ATP cycle, etc. When amyloid β (Aβ)-induced neurotoxicity occurs, the imbalance of actin dynamics leads to dystrophy of dendrites, which is characteristic pathology in Alzheimer’s disease (AD). Transient and persistent Aβ neurotoxicity provokes distinct manifestations of actin dynamics and causes opposing effects in AD. It has been shown that bone morphogenetic protein 6/7 (BMP6/7) protects neuronal morphology against Aβ-induced neurotoxicity, and can directly bind to LIM kinase1 (LIMK1), being one part of the upstream regulatory pathway of actin dynamics. This review aims to discuss a potential mechanism of BMPs underlying maintainance of cytoskeletal stabilization in neurite.

Inhibition of extracellular matrix assembly induces the expression of osteogenic markers in skeletal muscle cells by a BMP-2 independent mechanism
Nelson Osses, Juan Casar, Enrique Brandan
BMC Cell Biology , 2009, DOI: 10.1186/1471-2121-10-73
Abstract: Inhibition of proteoglycan sulfation by sodium chlorate in myoblast cultures strongly affects ECM synthesis and deposition and induces the expression of the osteogenic lineage markers alkaline phosphatase (ALP) and osteocalcin in mononuclear cells. Induction of ALP by sodium chlorate does not affect the expression of specific muscle determination transcription factors, such as MyoD and Myf-5, in the same cells. The osteogenic transcription factor Cbfa-1 expression is also unaffected. Induction of ALP is not inhibited by a soluble form of BMP receptor IA. This suggests that the deviation of the myogenic pathway of C2C12 myoblasts into the osteogenic lineage by inhibitors of proteoglycan sulfation is BMP-2 independent. The increase of osteogenic markers expression can be totally prevented by an exogenous ECM. Interestingly, a similar BMP-2-independent ALP activity induction can be observed in myoblasts cultured on an ECM previously synthesized by BMP-2 treated myoblasts. Under in vivo conditions of increased ECM turn-over and deposition, as in the mdx dystrophic muscle and during skeletal muscle regeneration, an induction and relocalization of ALP is observed in a subpopulation of skeletal muscle fibers, whereas in normal skeletal muscle, ALP expression is restricted to blood vessels and some endomysial mononuclear cells.These results suggest that signals arising from the ECM induce the expression of osteogenic markers in muscle cells by a mechanism independent of BMP-2 and without affecting the expression of key muscle or osteogenic determination genes. An induction and relocalization of ALP is also observed in mdx and regenerating skeletal muscles, in vivo conditions of increased muscle ECM deposition or turnover.Understanding the cellular and molecular basis of cell-determination and terminal differentiation is important as to gain insight into the mechanisms of normal development and, potentially, for the achievement of successful stem cell-based therapies. The ob
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