Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment

Abstract

Telomere shortening owing to telomerase deficiency leads to accelerated senescence of human skeletal (mesenchymal) stem cells (MSCs) in vitro, whereas overexpression leads to telomere elongation, extended life span, and enhanced bone formation. To study the role of telomere shortening in vivo, we studied the phenotype of telomerase-deficient mice (Terc À/À ). Terc À/À mice exhibited accelerated age-related bone loss starting at 3 months of age and during 12 months of follow-up revealed by dual-energy X-ray absorptiometric (DXA) scanning and by micro-computed tomography (mCT). Bone histomorphometry revealed decreased mineralized surface and boneformation rate as well as increased osteoclast number and size in Terc À/À mice. Also, serum total deoxypyridinoline (tDPD) was increased

Telomere Length and Aging

“…In addition, overexpression of proinflammatory genes involved in osteoclast differentiation was demonstrated by microarray screening. Thus, two mechanisms associate with bone deterioration with age have been demonstrated in telomerase deficient mice, suggesting presence of such a mechanism with aging: A) Bone cells damage and, B) Over expression of proinflammatory genes (Saeed et al, 2011). 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).…”

“…Early signs of dementia, family history and potentially modifiable risk factors as well as biological factors such as Telomere Length and telomerase dysfunction can serve as early disease markers. (Lukens et al, 2009;Saeed et al, 2011).…”

“…One of the phenotypes of this strain of mice is that they demonstrate accelerated rate of bone loss with age (Saeed et al, 2011). In cultured bone cells isolated from these mice, impaired osteogenic differentiation and reduced proliferation as well as accelerate senescence and DNA damage have been observed (Saeed et al, 2011).…”

Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) Directly Regulates Osteogenesis

“…MSC from NHERF1-null mice grown in osteogenic media had reduced osteoblast transcription factors and matrix proteins and mineralized poorly. Qualitative defects in osteoblast differentiation from MSC previously have been described in telomerase deficiency (34), when TNF alpha is pathologically high (35), or if TGF␤ and related proteins are suppressed (36). The NHERF1-null effect is the first example of a membrane regulatory protein defect that has similar consequences.…”

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

“…Altogether, these results show that mutations in Ft1 cause bone defects that partially phenocopy those observed in progeroid models caused by mutations in lamin coding genes or in genes involved in DNA metabolism (Bergo et al., 2002; Chen et al., 2012; Saeed et al., 2011). …”