Lowering circulating apolipoprotein E levels improves aged bone fracture healing

Ron, Huang; Zong, Xiao-Hua; Nadesan, Puviindran; Huebner, Janet L.; Kraus, Virginia B.; White, James P.; White, Phillip J.; Baht, Gurpreet S.

doi:10.1172/jci.insight.129144

Cited by 23 publications

(17 citation statements)

References 51 publications

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“…It has been shown in previous studies that apolipoprotein E expression is strongly induced upon differentiation and mineralization of osteoblasts 36 . Further studies have confirmed its role as a regulator for osteoblastogenesis and osteoclastogenesis in mice 37‐39 …”

Section: Discussionmentioning

confidence: 79%

Comparative proteomic analysis of osteogenic differentiated human adipose tissue and bone marrow‐derived stromal cells

Dadras

May

Wagner

et al. 2020

J Cellular Molecular Medi

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Section: Discussionmentioning

confidence: 79%

Comparative proteomic analysis of osteogenic differentiated human adipose tissue and bone marrow‐derived stromal cells

Dadras

May

Wagner

et al. 2020

J Cellular Molecular Medi

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“…Mutations in the APOE gene are associated with familial hypercholesterolemia associated with premature cardiovascular disease [134]. Reports about the positive effect of lowering APOE levels on the body, including age-related bone healing, are also more and more frequent [135]. Regarding MPS, changes in lipid metabolism and cholesterol levels [136] or its location [137] have been observed in MPS IIIA mice.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses

Rintz

Gaffke

Podlacha

et al. 2020

IJMS

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Although mucopolysaccharidoses (MPS), inherited metabolic diseases from the group of lysosomal storage diseases (LSD), are monogenic disorders, recent studies indicated that their molecular mechanisms are complicated. Storage of glycosaminoglycans (GAGs), arising from a deficiency in one of the enzymes involved in the degradation of these compounds, is the primary cause of each MPS type. However, dysfunctions of various cellular organelles and disturbance of cellular processes have been reported which contribute considerably to pathomechanisms of the disease. Here, we present a complex transcriptomic analysis in which all types and subtypes of MPS were investigated, with special emphasis on genes related to cell activation processes. Complex changes in expression of these genes were found in fibroblasts of all MPS types, with number of transcripts revealing higher or lower levels (relative to control fibroblasts) between 19 and over 50, depending on MPS type. Genes in which expression was significantly affected in most MPS types code for proteins involved in following processes, classified according to Gene Ontology knowledge database: cell activation, cell growth, cell recognition, and cell division. Levels of some transcripts (including CD9, CLU, MME and others) were especially significantly changed (over five times relative to controls). Our results are discussed in the light of molecular pathomechanisms of MPS, indicating that secondary and/or tertiary changes, relative to GAG storage, might significantly modulate cellular dysfunctions and contribute to molecular mechanisms of the disease. This may influence the efficacy of various therapies and suggests why various treatments are not fully effective in improving the complex symptoms of MPS.

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“…Fractures were performed as previously described. 23 , 24 Briefly, mice were anesthetized and the surgical area proximal to the knee was shaved and disinfected. Following an incision, a hole was drilled into the tibial plateau and a 0.7 mm stainless steel pin was placed into the medullary cavity and cut flush with the tibial plateau.…”

Section: Methodsmentioning

confidence: 99%

Maresin 1 resolves aged‐associated macrophage inflammation to improve bone regeneration

Ron

Zong

et al. 2020

FASEB j.

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Inflammaging is associated with poor tissue regeneration observed in advanced age. Specifically, protracted inflammation after acute injury has been associated with decreased bone fracture healing and increased rates of nonunion in elderly patients. Here, we investigated the efficacy of using Maresin 1 (MaR1), an omega‐3 fatty acid‐derived pro‐resolving agent, to resolve inflammation after tibial fracture injury and subsequently improving aged bone healing. Aged (24‐month‐old mice) underwent tibial fracture surgery and were either treated with vehicle or MaR1 3 days after injury. Fracture calluses were harvested 7 days, 14 days, 21 days, and 28 days after injury to investigate inflammatory response, cartilage development, bone deposition, and mechanical integrity, respectively. Healing bones from MaR1‐treated mice displayed decreased cartilage formation and increased bone deposition which resulted in increased structural stiffness and increased force to fracture in the later stages of repair. In the early stages, MaR1 treatment decreased the number of pro‐inflammatory macrophages within the fracture callus and decreased the level of inflammatory biomarkers in circulation. In tissue culture models, MaR1 treatment of bone marrow‐derived macrophages from aged mice protected cells form a pro‐inflammatory phenotype and induced an anti‐inflammatory fate. Furthermore, the secretome of MaR1‐treated bone marrow‐derived macrophages was identified as osteoinductive, enhancing osteoblast differentiation of bone marrow stromal cells. Our findings here identify resolution of inflammation, and MaR1 itself, to be a point of intervention to improve aged bone healing.

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Lowering circulating apolipoprotein E levels improves aged bone fracture healing

Cited by 23 publications

References 51 publications

Comparative proteomic analysis of osteogenic differentiated human adipose tissue and bone marrow‐derived stromal cells

Comparative proteomic analysis of osteogenic differentiated human adipose tissue and bone marrow‐derived stromal cells

Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses

Maresin 1 resolves aged‐associated macrophage inflammation to improve bone regeneration

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