Sclerosteosis

Stein, Stuart A.; Witkop, Carl J.; Hill, Suvimol; Fallon, Michael D.; Viernstein, Lawrence J.; Gücer, G.; McKeever, Paul E.; Long, Donlin M.; Altman, Joanne D.; Miller, Neil R.; Teitelbaum, Steven L.; Schlesinger, Sandra

doi:10.1212/wnl.33.3.267

Cited by 94 publications

(59 citation statements)

References 20 publications

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“…In addition, limited histomorphometric data reported from a single sclerosteosis patient demonstrated that the bone-formation rate was more than 9 SDs above the normal range and that the number of osteoclasts per area of bone tissue was within the low to normal range, suggestive of an uncoupling between osteoblasts and osteoclasts. (30) For sclerostin inhibition (genetic and pharmacologic), it is unclear whether this uncoupling is from a direct effect on osteoclasts or secondary to the a marked increase in bone-forming surface. This mode of anabolism may differ from that found in PTH treatment studies, in which bone-resorption markers in humans (31) and primates (32) were increased 1 month after administration.…”

Section: Discussionmentioning

confidence: 99%

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody

Padhi

Jang

Stouch

et al. 2010

Journal of Bone and Mineral Research

692

529

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Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation. ß

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Section: Discussionmentioning

confidence: 99%

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody

Padhi

Jang

Stouch

et al. 2010

Journal of Bone and Mineral Research

692

529

View full text Add to dashboard Cite

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“…Syndactyly and gigantism are also frequently found in patients with SOST1, and the appearance of a square-shaped jaw is a common facial feature (Beighton 1988). Heterozygous carriers are only mildly affected and display age-related thickening of the calvaria, mandible, ribs, clavicles, and long bones with increased bone mineral density in otherwise clinically inconspicuous individuals (Beighton et al 1977;Stein et al 1983;Gardner et al 2005).…”

Section: Gain Of Bone Mass In Camurati -Engelmann Diseasementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…This apparent lack of coupling was also reported for SOST knockout mice (18) and is consistent with the very limited (one patient) histomorphometric data available for sclerosteosis. (75) Currently, it is unclear whether the reduction in osteoclast surface resulting from antibody-mediated sclerostin inhibition is from a direct impact on osteoclasts or secondary to the marked increase in bone-forming surface. Another interesting feature of pharmacologic sclerostin inhibition in OVX rats is that the strong anabolic effect comes largely from activation of bone formation on quiescent surfaces (bone modeling), with much smaller contributions coming from bone formation on remodeling surfaces.…”

Section: Pharmacology Of Sclerostin Antibodiesmentioning

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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Sclerosteosis

Cited by 94 publications

References 20 publications

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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

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