Biochemical Markers of Bone Turnover in Camurati–Engelmann Disease: A Report on Four Cases in One Family

Hernández, M. Victoria; Peris, Pilar; Guañabens, Núria; Álvarez, Luisa; Monegal, Ana; Pons, Françesca; Ponce, Andrés; Múñoz-Gómez, J

doi:10.1007/s002239900293

Cited by 32 publications

(21 citation statements)

References 19 publications

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“…Although CED is characterized by a net increase in bone mass in some regions of the skeleton, bone resorption is also increased, as reflected by biochemical markers of bone resorption that are increased 3-to 10-fold above the normal range in affected patients (11). This indicates that the activating mutations of TGF␤1 that cause CED result in a state of increased bone turnover, rather than just an increase in bone formation.…”

Section: Discussionmentioning

confidence: 99%

A Mutation Affecting the Latency-Associated Peptide of TGFβ1 in Camurati-Engelmann Disease Enhances Osteoclast Formationin Vitro

McGowan

MacPherson

Janssens

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

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Camurati-Engelmann disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFbeta type II receptor. Total serum TGFbeta1 levels were similar in affected and unaffected subjects, but concentrations of active TGFbeta1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFbeta1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.

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Section: Discussionmentioning

confidence: 99%

A Mutation Affecting the Latency-Associated Peptide of TGFβ1 in Camurati-Engelmann Disease Enhances Osteoclast Formationin Vitro

McGowan

MacPherson

Janssens

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

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“…Clinical manifestations do not include fibrosis or aneurysm, and no evidence for increased TGF-b signaling has been described in the aortic wall or other tissues, suggesting that these mutations have tissue-specific effects on TGF-b activity. It appears that patients with CED have increased rates of bone resorption as well as bone formation, with the overall balance shifted toward bone formation, possibly because of increased proliferation of osteoblasts (Hernandez et al 1997;Saito et al 2001;McGowan et al 2003). CED can be successfully treated with glucocorticosteroids, which decrease proliferation, maturation and ECM synthesis in osteoblasts and osteocytes, and also increase the rate of apoptosis of these cells, thus resulting in a net decrease in bone mass (Low et al 1985;Naveh et al 1985).…”

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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“…CED is a rare autosomal dominant genetic disorder characterized by hyperostosis and sclerosis, especially affecting the diaphysis of long bones. Clinically, CED is characterized by radiological osteosclerosis, but affected patients also have increased markers of bone resorption, suggesting that bone resorption is elevated as well as bone formation (Hernandez et al 1997). The causal gene for CED was mapped to chromosome 19q13 by linkage analysis Janssens et al 2000b), and then mutations in TGFB1 were identified as a cause using a positional candidate approach (Janssens et al 2000a;Kinoshita et al 2000).…”

Section: Transforming Growth Factor Tgf-␤1mentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

291

229

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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Biochemical Markers of Bone Turnover in Camurati–Engelmann Disease: A Report on Four Cases in One Family

Cited by 32 publications

References 19 publications

A Mutation Affecting the Latency-Associated Peptide of TGFβ1 in Camurati-Engelmann Disease Enhances Osteoclast Formationin Vitro

A Mutation Affecting the Latency-Associated Peptide of TGFβ1 in Camurati-Engelmann Disease Enhances Osteoclast Formationin Vitro

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Genetic regulation of bone mass and susceptibility to osteoporosis

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