mTOR signaling in skeletal development and disease

Chen, Jianquan; Long, Fanxin

doi:10.1038/s41413-017-0004-5

Cited by 221 publications

(203 citation statements)

References 83 publications

Supporting

Mentioning

197

Contrasting

Order By: Relevance

“…Development of normal skeletal bone is a complex and strictly organized physiological process. Bone tissue heals through two separate regenerative pathways: endochondral and intramembranous ossification . During this process, tissue‐derived mesenchymal stem cells (MSCs) cooperate to repair bone through specific interactions involving paracrine properties or their direct differentiation into osteoblasts, chondrocytes or adipocytes.…”

Section: Molecular Mechanisms In Heterotopic Ossificationmentioning

confidence: 99%

Challenges of heterotopic ossification—Molecular background and current treatment strategies

Łęgosz

Drela

Pulik

et al. 2018

Clin Exp Pharma Physio

View full text Add to dashboard Cite

Heterotopic ossification (HO) is an abnormal formation of mature lamellar bone within extraskeletal soft tissues, such as muscles, tendons, and ligaments. This process is thought to be induced by inflammation associated with tissue injuries. HO is classified using two subtypes: resulting from injury or genetically inherited. HO formation is associated with polytrauma patients with traumatic brain injuries and spinal cord injuries. Moreover, HO is also considered to be a post-operative risk factor in some orthopaedic procedures. In this review, we summarize our current understanding of the pathology of different types of HO and discuss its current and future therapies. Thus far, research has revealed cellular and molecular pathways leading to HO formation and proposed several possible mechanisms leading to HO and conserved signalling pathways common in the different HO subtypes. Non-steroidal anti-inflammatory drug treatment and localized low-dose irradiation are currently the only available prophylactic treatments for HO. However, they are not always effective and do not target the osteogenic processes directly. New therapeutic strategies targeting the pathological processes of HO, such as bone morphogenetic protein (BMP) inhibitors like noggin, BMP type 1 receptor inhibitor, and nuclear retinoid acid receptor-gamma (RARγ) agonists, are currently being investigated. In-depth understanding of the HO pathological process could help to develop effective therapeutic strategies.

show abstract

Section: Molecular Mechanisms In Heterotopic Ossificationmentioning

confidence: 99%

Challenges of heterotopic ossification—Molecular background and current treatment strategies

Łęgosz

Drela

Pulik

et al. 2018

Clin Exp Pharma Physio

View full text Add to dashboard Cite

show abstract

“…The three other common pathways, Amoebiasis, Glioma, and Lysine degradation, have no obvious function in bone and may be the result of miRNA targets being common to several functional pathways. For example, the glioma pathway includes miRNA targets such as mammalian target of rapamycin ( MTOR ), platelet‐derived growth factor receptor alpha ( PDGFRA ), and epidermal growth factor ( EGF ), which have established functions in bone metabolism . The ECM–receptor interaction pathway involves interactions between various cell‐associated integrins and matrix collagens which are central actors in bone metabolism.…”

Section: Discussionmentioning

confidence: 99%

Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture, Studied in Weight-Bearing and Non–Weight-Bearing Human Bone

Gautvik

Günther

Prijatelj

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

We investigated mechanisms resulting in low bone mineral density (BMD) and susceptibility to fracture by comparing noncoding RNAs (ncRNAs) in biopsies of non–weight‐bearing (NWB) iliac (n = 84) and weight bearing (WB) femoral (n = 18) postmenopausal bone across BMDs varying from normal (T‐score > −1.0) to osteoporotic (T‐score ≤ −2.5). Global bone ncRNA concentrations were determined by PCR and microchip analyses. Association with BMD or fracture, adjusted by age and body mass index, were calculated using linear and logistic regression and least absolute shrinkage and selection operator (Lasso) analysis. At 10% false discovery rate (FDR), 75 iliac bone ncRNAs and 94 femoral bone ncRNAs were associated with total hip BMD. Eight of the ncRNAs were common for the two sites, but five of them (miR‐484, miR‐328‐3p, miR‐27a‐5p, miR‐28‐3p, and miR‐409‐3p) correlated positively to BMD in femoral bone, but negatively in iliac bone. Of predicted pathways recognized in bone metabolism, ECM‐receptor interaction and proteoglycans in cancer emerged at both sites, whereas fatty acid metabolism and focal adhesion were only identified in iliac bone. Lasso analysis and cross‐validations identified sets of nine bone ncRNAs correlating strongly with adjusted total hip BMD in both femoral and iliac bone. Twenty‐eight iliac ncRNAs were associated with risk of fracture (FDR < 0.1). The small nucleolar RNAs, RNU44 and RNU48, have a function in stabilization of ribosomal RNAs (rRNAs), and their association with fracture and BMD suggest that aberrant processing of rRNAs may be involved in development of osteoporosis. Cis‐eQTL (expressed quantitative trait loci) analysis of the iliac bone biopsies identified two loci associated with microRNAs (miRNAs), one previously identified in a heel‐BMD genomewide association study (GWAS). In this comprehensive investigation of the skeletal genetic background in postmenopausal women, we identified functional bone ncRNAs associated to fracture and BMD, representing distinct subsets in WB and NWB skeletal sites. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

show abstract

“…In mice, administration of the mTOR inhibitor rapamycin increases healthspan and is the most robust intervention to increase lifespan . mTORC1 and mTORC2 perform important functions in bone development . Genetic disruption of mTORC1 in the osteoblast lineage inhibits the transition of preosteoblasts to mature osteoblasts, and prevents the accrual of normal bone mass or the response to Wnt‐induced bone anabolism in mice .…”

Section: Deregulated Nutrient Sensingmentioning

confidence: 99%

“…(87) mTORC1 and mTORC2 perform important functions in bone development. (88) Genetic disruption of mTORC1 in the osteoblast lineage inhibits the transition of preosteoblasts to mature osteoblasts, and prevents the accrual of normal bone mass or the response to Wnt-induced bone anabolism in mice. (89,90) Accordingly, constitutive activation of mTORC1 increases osteoblast number and bone formation.…”

Section: Foxosmentioning

confidence: 99%

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

Farr

Almeida

2018

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Aging research has undergone unprecedented advances at an accelerating rate in recent years, leading to excitement in the field as well as opportunities for imagination and innovation. Novel insights indicate that, rather than resulting from a preprogrammed series of events, the aging process is predominantly driven by fundamental non-adaptive mechanisms that are interconnected, linked, and overlap. To varying degrees, these mechanisms also manifest with aging in bone where they cause skeletal fragility. Because these mechanisms of aging can be manipulated, it might be possible to slow, delay, or alleviate multiple age-related diseases and their complications by targeting conserved genetic signaling pathways, controlled functional networks, and basic biochemical processes. Indeed, findings in various mammalian species suggest that targeting fundamental aging mechanisms (eg, via either loss-of-function or gain-of-function mutations or administration of pharmacological therapies) can extend healthspan; ie, the healthy period of life free of chronic diseases. In this review, we summarize the evidence supporting the role of the spectrum of fundamental basic science discoveries contributing to organismal aging, with emphasis on mammalian studies and in particular aging mechanisms in bone that drive skeletal fragility. These mechanisms or aging hallmarks include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Because these mechanisms are linked, interventions that ameliorate one hallmark can in theory ameliorate others. In the field of bone and mineral research, current challenges include defining the relative contributions of each aging hallmark to the natural skeletal aging process, better understanding the complex interconnections among the hallmarks, and identifying the most effective therapeutic strategies to safely target multiple hallmarks. Based on their interconnections, it may be feasible to simultaneously interfere with several fundamental aging mechanisms to alleviate a wide spectrum of age-related chronic diseases, including osteoporosis. © 2018 American Society for Bone and Mineral Research.

show abstract

mTOR signaling in skeletal development and disease

Cited by 221 publications

References 83 publications

Challenges of heterotopic ossification—Molecular background and current treatment strategies

Challenges of heterotopic ossification—Molecular background and current treatment strategies

Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture, Studied in Weight-Bearing and Non–Weight-Bearing Human Bone

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

Contact Info

Product

Resources

About