Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis

Pignolo, Robert J.; Suda, Robin K.; McMillan, Emily A.; Shen, Johnny; Lee, Seoung Hoon; Choi, Yongwon; Wright, Alexander C.; Johnson, F. Brad

doi:10.1111/j.1474-9726.2007.00350.x

Cited by 127 publications

(111 citation statements)

References 32 publications

(44 reference statements)

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…The relevance of telomere shortening to in vivo aging is demonstrated by the presence of an osteoporotic phenotype in patients with excessive telomere shortening and telomere dysfunction (e.g., Werner's syndrome and Dyskeratosis congenita) (Vulliamy et al, 2001;Crabbe et al, 2007). Furthermore, mice carrying the Werner mutation on a background of short telomeres (Wrn) ⁄ ) Terc) ⁄ ) deficient mouse) exhibit a low bone mass phenotype (Pignolo et al, 2008). In normal human populations, bone mass measured by DEXA exhibits a small but significant correlation with telomere length of peripheral blood leukocytes (Valdes et al, 2007).…”

Section: Telomerase Deficiency and Telomere Shorteningmentioning

confidence: 99%

Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions

Kassem¹,

Marie²

2011

Aging Cell

194

154

View full text Add to dashboard Cite

SummaryHuman aging is associated with bone loss leading to bone fragility and increased risk of fractures. The cellular and molecular causes of age-related bone loss are current intensive topic of investigation with the aim of identifying new approaches to abolish its negative effects on the skeleton. Age-related osteoblast dysfunction is the main cause of age-related bone loss in both men and women beyond the fifth decade and results from two groups of pathogenic mechanisms: extrinsic mechanisms that are mediated by age-related changes in bone microenvironment including changes in levels of hormones and growth factors, and intrinsic mechanisms caused by the osteoblast cellular senescence. The aim of this review is to provide a summary of the intrinsic senescence mechanisms affecting osteoblastic functions and how they can be targeted to abolish age-related osteoblastic dysfunction and bone loss associated with aging.

show abstract

Section: Telomerase Deficiency and Telomere Shorteningmentioning

confidence: 99%

Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions

Kassem¹,

Marie²

2011

Aging Cell

194

154

View full text Add to dashboard Cite

show abstract

“…Similar observation of low bone mass phenotype and age-related osteoporosis has been reported in double knockout mice (the telomerase deficient and Wrn helicase which caused premature aging). In addition, mesenchymal stem cells (MSCs) from the double knockout mice have a short lifespan and impaired osteogenic in vitro (Pignolo et al, 2008).…”

Section: Telomere and Bone Structurementioning

confidence: 99%

Telomere Length and Aging

Muzumdar¹,

Atzmon²

2012

Reviews on Selected Topics of Telomere Biology

View full text Add to dashboard Cite

“…In vitro, TBD-BMSCs had decreased CFE, indicating a reduced frequency of clonogenic SSCs/ BMSCs, as has been found in TERC-deficient mice. 40,41 Decreased CFE was also reflected by poor proliferation of TBD-BMSCs, along with accelerated senescence, which has also been described in TERCdeficient mice. 40,41 Furthermore, TBD-BMSCs exhibited changes in differentiation potential, reflected by their spontaneous differentiation into adipocytes, and in some cases, collagen-depositing fibroblasts (2 patients from 1 kindred), both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 68%

“…40,41 Decreased CFE was also reflected by poor proliferation of TBD-BMSCs, along with accelerated senescence, which has also been described in TERCdeficient mice. 40,41 Furthermore, TBD-BMSCs exhibited changes in differentiation potential, reflected by their spontaneous differentiation into adipocytes, and in some cases, collagen-depositing fibroblasts (2 patients from 1 kindred), both in vitro and in vivo. However, fibrosis was noted in cells from mutation-free siblings in that kindred, therefore we cannot rule out a non-TBD cause, but we report the findings here based on the fact that many patients with TBD exhibit pulmonary and liver fibrosis.…”

Section: Discussionmentioning

confidence: 68%

Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders

Balakumaran

Mishra

Pawelczyk

et al. 2015

Blood

View full text Add to dashboard Cite

• BMSCs from patients with TBDs are abnormal and unable to support hematopoiesis.• Knockdown of TERC with siRNA recapitulates the TBD-BMSC phenotype.Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD. (Blood. 2015;125(5):793-802)

show abstract

Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis

Cited by 127 publications

References 32 publications

Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions

Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions

Telomere Length and Aging

Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders

Contact Info

Product

Resources

About