The Loss of Smad3 Results in a Lower Rate of Bone Formation and Osteopenia Through Dysregulation of Osteoblast Differentiation and Apoptosis

Borton, Anita J.; Frederick, Joshua P.; Datto, Michael B.; Wang, Xiaofan; Weinstein, Robert S.

doi:10.1359/jbmr.2001.16.10.1754

Cited by 167 publications

(141 citation statements)

References 52 publications

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“…Because bone mass is reduced in Smad3Ϫ͞Ϫ mice (14,17) but increased in DNT␤RII mice (16), our results also illustrate that the mechanical properties of bone matrix are independent of macrostructural changes in the tissue. Although previous reports had not differentiated Smad3ϩ͞Ϫ from wild-type bone (14,17), the elastic modulus and hardness of Smad3ϩ͞Ϫ bone were as high as the Smad3Ϫ͞Ϫ bone values. In contrast, D4 and D5 mice with elevated TGF-␤ signaling had lower elastic modulus and hardness, reduced by 24% and 16%, respectively, compared with wild-type littermates.…”

Section: Tgf-␤ Regulates the Mechanical Properties Of Bone Matrixmentioning

confidence: 52%

“…Because regulators of bone matrix properties have not been identified, and TGF-␤ regulates bone mass and architecture and the expression of bone matrix proteins (6,(14)(15)(16)(17), we examined whether TGF-␤ regulates the material properties of bone matrix. We used transgenic mice with mutations in TGF-␤ signaling, including D4, D5, DNT␤RII, Smad3ϩ͞Ϫ, and Smad3Ϫ͞Ϫ mice.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, DNT␤ RII mice, which express a ''dominant negative'' type II TGF-␤ receptor in osteoblasts, show decreased TGF-␤ responsiveness in osteoblasts and increased bone volume (16). Smad3Ϫ͞Ϫ mice, which are defective in the expression of Smad3 in all tissues, also have a bone phenotype with an osteopenic reduction in bone volume (14,17). In addition to the direct role of TGF-␤͞Smad3 signaling in bone metabolism, some aspects of the Smad3Ϫ͞Ϫ bone phenotype may be due to immune, gastrointestinal, or endocrine defects associated with systemic loss of Smad3 expression (24)(25)(26).…”

Section: Resultsmentioning

confidence: 99%

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TGF-β regulates the mechanical properties and composition of bone matrix

Balooch

Nalla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

200

191

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The characteristic toughness and strength of bone result from the nature of bone matrix, the mineralized extracellular matrix produced by osteoblasts. The mechanical properties and composition of bone matrix, along with bone mass and architecture, are critical determinants of a bone's ability to resist fracture. Several regulators of bone mass and architecture have been identified, but factors that regulate the mechanical properties and composition of bone matrix are largely unknown. We used a combination of high-resolution approaches, including atomic-force microscopy, x-ray tomography, and Raman microspectroscopy, to assess the properties of bone matrix independently of bone mass and architecture. Properties were evaluated in genetically modified mice with differing levels of TGF-␤ signaling. Bone matrix properties correlated with the level of TGF-␤ signaling. Smad3؉͞؊ mice had increased bone mass and matrix properties, suggesting that the osteopenic Smad3؊͞؊ phenotype may be, in part, secondary to systemic effects of Smad3 deletion. Thus, a reduction in TGF-␤ signaling, through its effector Smad3, enhanced the mechanical properties and mineral concentration of the bone matrix, as well as the bone mass, enabling the bone to better resist fracture. Our results provide evidence that bone matrix properties are controlled by growth factor signaling.osteoblast ͉ Smad3 ͉ atomic force microscopy T he ability of bones to resist fracture is determined by the bone mass and architecture, and the mechanical properties and composition of the bone matrix (1). Bone architecture is determined by cortical bone thickness, trabecular bone volume, and organization. Several signaling pathways, including estrogen, parathyroid hormone, and TGF-␤, have been implicated in the control of bone mass and architecture and its deregulation in metabolic bone diseases such as osteoporosis (2, 3). Much less is known about the mechanical properties and composition of bone matrix, the unique protein-and mineral-rich extracellular material produced by osteoblasts and osteocytes. However, the importance of bone matrix quality is clinically apparent in bone disorders such as osteogenesis imperfecta and osteopetrosis (4, 5). Osteopetrosis patients have increased bone fragility despite elevated bone mass (4). Presumably, bone matrix properties are highly regulated, but the regulators themselves are unknown, partly because of the inaccessibility of methods to define these properties independently of bone mass and architecture. Nevertheless, the regulation of bone matrix properties must be understood to more effectively treat bone disorders.TGF-␤ plays stage-dependent roles in osteoblast and osteoclast differentiation. TGF-␤ inhibits osteoblast differentiation yet stimulates the proliferation of mesenchymal progenitors, thereby expanding the cell population that will differentiate into osteoblasts (6). TGF-␤ signals through a complex of type I and type II transmembrane serine͞threonine kinases (7). Upon ligand binding, the receptor complex phosphorylat...

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Section: Tgf-␤ Regulates the Mechanical Properties Of Bone Matrixmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

TGF-β regulates the mechanical properties and composition of bone matrix

Balooch

Nalla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

200

191

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show abstract

“…Inactivation of components of the TGF-␤ pathway frequently results in embryonic lethality, but TGF-␤1-null mice develop generalized inflammation and decreased bone mass with a pronounced reduction of the number of osteoblasts (Geiser et al 1998). In addition, Smad3-null mice show osteopenia, which is thought to be due to excessive late-phase osteoblast differentiation into osteocytes and concomitant apoptosis (Borton et al 2001). …”

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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“…62 Mice lacking Smad3 live until 8 months and die of defects in immune function. 63 These mice also have an imbalance between osteoblasts and osteoclasts resulting in osteopenia 63 and accelerated healing of cutaneous incisional wounds. 64 Exposure of these mice to radiation-induced injury causes significantly less epidermal acanthosis and dermal influx of mast cells, macrophages, and neutrophils than wild type littermates, demonstrating that these mice have a significantly reduced fibrotic response.…”

Section: Tgf-β Knockout Micementioning

confidence: 99%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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Transforming growth factor-β (TGF-β) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-βs useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-β has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-β have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-β activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.

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The Loss of Smad3 Results in a Lower Rate of Bone Formation and Osteopenia Through Dysregulation of Osteoblast Differentiation and Apoptosis

Cited by 167 publications

References 52 publications

TGF-β regulates the mechanical properties and composition of bone matrix

TGF-β regulates the mechanical properties and composition of bone matrix

Genetic regulation of bone mass and susceptibility to osteoporosis

Medical Applications of Transforming Growth Factor-

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