Osteocyte control of bone formation via sclerostin, a novel BMP antagonist

Winkler, David G.; Sutherland, May Kung; Geoghegan, James C.; Yu, Changpu; Hayes, Trenton; Skonier, John E.; Shpektor, Diana; Jonas, Mechtild; Kovacevich, Brian R.; Staehling‐Hampton, Karen; Appleby, Mark W.; Brunkow, Mary E.; Latham, John

doi:10.1093/emboj/cdg599

Cited by 991 publications

(887 citation statements)

References 81 publications

(43 reference statements)

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“…Although it is not yet clear whether Scl-Ab had any direct effects on the formation or removal of cartilage, sclerostin expression has been detected in hypertrophic chondrocytes in human tissue. (14) The development of a cartilaginous callus depends in part on the amount of motion at the fracture site, with a transition to bone once the fracture has been stabilized sufficiently. (1) Thus, if Scl-Ab resulted in an earlier stabilization of the fracture, it should result in a more mature callus by the end of the study.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

Ominsky

et al. 2010

Journal of Bone and Mineral Research

240

212

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Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator of bone formation, and treatment with a sclerostin monoclonal antibody (Scl-Ab) results in increased bone formation and bone mass in animal models. Our objective was to investigate the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results support the potential for systemic Scl-Ab administration to enhance fracture healing in patients. ß

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Section: Discussionmentioning

confidence: 99%

“…(11)(12)(13)(14) Humans with inherited sclerostin deficiency (sclerosteosis or van Buchem disease) have increased bone mass and are resistant to fracture. (15,16) Sclerostin knockout mice have greater bone mass and bone strength owing to increased bone formation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

Ominsky

et al. 2010

Journal of Bone and Mineral Research

240

212

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“…(39,42,53) These terminally differentiated cells of the osteoblast lineage are found embedded within bone matrix throughout the entire skeleton and are the most abundant cell type in bone. With their extensive cytoplasmic connections to one another and to osteoblasts and bone-lining cells located on bone surfaces, osteocytes form an interconnected network and had been postulated to act as bone mechanosensors.…”

Section: Osteocytes Mechanical Loading and Interface With The Pth Pmentioning

confidence: 99%

“…In addition to these Wnt pathway findings, sclerostin had been reported to regulate the bone morphogenetic protein (BMP) pathway by binding to and antagonizing the activity of BMPs, (39,40) as well as Noggin, (41) itself a well-known BMP antagonist.…”

mentioning

confidence: 99%

Sclerostin: A gem from the genome leads to bone-building antibodies

Pászty

Turner

Robinson

2010

Journal of Bone and Mineral Research

113

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Discovery of SclerostinG enomics technologies and DNA sequencing have had a transformative impact on biological research, giving us unprecedented access to the genomes of numerous organisms and ushering in such new fields as systems biology (1) and, more recently, synthetic biology. (2,3) In the 1990s, the advent of highthroughput sequencing spurred application of this powerful new technology to the challenging endeavor of trying to understand the genetic basis of various inherited human diseases. One such disease was sclerosteosis, a very rare, recessively inherited highbone-mass disorder that was thought to be caused primarily by excessive osteoblast-mediated bone formation rather than by defective osteoclast-mediated bone resorption. (4,5) Within the realm of inherited high-bone-mass disorders, (6) it was the hope for a discovery in the area of osteoblast biology that made sclerosteosis particularly interesting.Indeed, the identification of new bone-building pathways that might yield novel anabolic agents had been a long-standing goal in bone biology, with hopes for therapeutic application in fracture healing, orthopedic procedures, and low-bone-mass conditions such as osteoporosis. Against this backdrop came the exciting news, independently from Mary Brunkow's group at Celltech R&D, Inc., (7,8) and from Wim Van Hul's group at the University of Antwerp, (9) that sclerosteosis was caused by mutations in a single gene (SOST) encoding a novel secreted protein. Because these were inactivating mutations, it was clear that this protein, aptly given the name sclerostin, functioned either directly or indirectly as an inhibitor of bone formation. During this same general time period, large-scale cDNA/ expressed sequence tag (EST) (10)(11)(12) and genomic DNA sequencing efforts were being made in academia and industry to rapidly identify new human genes. A novel secreted protein of unknown function, which turned out to be sclerostin, was discovered by computational mining of large DNA sequence databases using either homology-based programs (eg, BLAST) (13,14) or a special CxGxC-class cystine-knot search pattern (C Paszty, unpublished) (15) designed to identify new families of cystine-knot proteins. (16,17) Thus sclerostin emerged during an exciting era of gene discovery that was fueled, in part, by the development of important genomics technologies and the advent of high-throughput DNA sequencing.Similar to sclerostin inactivation in humans, mice with a targeted deletion of the sclerostin gene (SOST knockout mice) were found to have high bone mass, demonstrating evolutionary conservation of sclerostin's function as a negative regulator of bone formation. (18) Analysis of bones from these mice revealed that bone formation was markedly increased on each of the key skeletal surfaces where new bone is normally formed (surface of trabecular bone and internal and external surfaces of cortical bone). Consistent with the increases in bone formation and bone mass, robust increases in bone strength also were found in these anima...

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“…In contrast to this 'stimulatory' model, it was found in recent years that osteocytes inhibit bone formation via the protein sclerostin (Winkler et al 2003;van Bezooijen et al 2007). To reconcile this information with strain-induced bone formation, one needs to assume that sclerostin production by osteocytes decreases with mechanical loading.…”

mentioning

confidence: 98%

A sclerostin-based theory for strain-induced bone formation

Oers

Rietbergen

Ito

et al. 2010

Biomech Model Mechanobiol

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Bone formation responds to mechanical loading, which is believed to be mediated by osteocytes. Previous theories assumed that loading stimulates osteocytes to secrete signals that stimulate bone formation. In computer simulations this 'stimulatory' theory successfully produced loadaligned trabecular structures. In recent years, however, it was discovered that osteocytes inhibit bone formation via the protein sclerostin. To reconcile this with strain-induced bone formation, one must assume that sclerostin secretion decreases with mechanical loading. This leads to a new 'inhibitory' theory in which loading inhibits osteocytes from inhibiting bone formation. Here we used computer simulations to show that a sclerostin-based model is able to produce a load-aligned trabecular architecture. An important difference appeared when we compared the response of the stimulatory and inhibitory models to loss of osteocytes, and found that the inhibitory pathway prevents the loss of trabeculae that is seen with the stimulatory model. Further, we demonstrated with combined stimulatory/inhibitory models that the two pathways can work side-by-side to achieve a load-adapted bone architecture.

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Osteocyte control of bone formation via sclerostin, a novel BMP antagonist

Cited by 991 publications

References 81 publications

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

Sclerostin: A gem from the genome leads to bone-building antibodies

A sclerostin-based theory for strain-induced bone formation

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