Local communication on and within bone controls bone remodeling

Henriksen, Kim; Neutzsky-Wulff, Anita V.; Bonewald, Lynda F.; Karsdal, Morten A.

doi:10.1016/j.bone.2009.03.671

Cited by 247 publications

(230 citation statements)

References 138 publications

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“…11,12 Importantly, the molecular pathways that regulate differentiation of bone cells are coordinated through cross-talks among neighboring stromal cells. 13 Thus, it is not surprising that general disruptions within the miRNA biogenesis machinery described above would have dramatic impacts on physiological bone remodeling. Interestingly, a number of recent studies have revealed the capacity for individual miRNAs to direct the differentiation and activity of cells residing in the bone microenvironment ( Figure 1a).…”

Section: A Central Role For Mirnas In Bone Homeostasismentioning

confidence: 99%

MicroRNAs as regulators of bone homeostasis and bone metastasis

Ell

Kang

2014

Bonekey Reports

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MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.BoneKEy Reports 3, Article number: 549 (2014) | doi:10.1038/bonekey.2014.44 MiRNA Biogenesis and FunctionThe past decade has seen a torrent of novel research into the post-translational regulation of genes via microRNA-mediated suppression. The microRNAs (miRNAs) are a class of B22-nucleotide-long RNAs that repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 1 Mature miRNAs are generated by the sequential cleavage of longer precursor transcripts, or pri-miRNAs, that are typically transcribed from intragenic or intergenic regions by RNA polymerase II. 2 The initial cleavage step, mediated by Drosha and the DGCR8 complex, occurs in the nucleus and produces a shortened (70-100 nucleotides) pre-miRNA hairpin. Pre-miRNAs are exported from the nucleus by Exportin 5, followed by a second cleavage by the ribonuclease Dicer that produces a double-stranded, B18-25-nucleotide-long mature miRNA. One miRNA strand will then combine with Argonaute (AGO2) proteins to produce an RNAinduced silencing complex, allowing for directed pairing with target mRNAs. 1

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Section: A Central Role For Mirnas In Bone Homeostasismentioning

confidence: 99%

MicroRNAs as regulators of bone homeostasis and bone metastasis

Ell

Kang

2014

Bonekey Reports

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“…It is known that bone is formed in areas where loads are elevated and bone is necessary, and resorbed where strains and stresses are absent and bone is excessive. [3][4][5] Many experimental data in vitro and in vivo indicate the osteocytes as the main sensor detecting mechanical forces in the bone tissue. [6][7][8][9] Osteocytes comprise 90-95% of all bone cells in the adult skeleton, and they are located in the mineralized bone matrix within lacunae.…”

Section: The Effect Of Mechanical Strain On Soft (Cardiovascular) Andmentioning

confidence: 99%

The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

Boccafoschi

Mosca

Ramella

et al. 2013

Cell Adhesion & Migration

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“…Bone homeostasis and skeletal integrity require a tightly regulated equilibrium between the activity of bone-resorbing osteoclasts and bone-forming osteoblasts (1,2). Osteoporosis is a disease where imbalance between both processes leads to low bone mineral density (BMD) 5 and deterioration of bone structure.…”

mentioning

confidence: 99%

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

Leupin

Piters

Halleux

et al. 2011

Journal of Biological Chemistry

273

245

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Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. Although it is well established that sclerostin is an osteocyte-secreted bone formation inhibitor, the underlying molecular mechanisms are not fully elucidated. We identified in tandem affinity purification proteomics screens LRP4 (low density lipoprotein-related protein 4) as a sclerostin interaction partner. Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/␤-catenin signaling. We found the extracellular ␤-propeller structured domain of LRP4 to be required for this sclerostin facilitator activity. Immunohistochemistry demonstrated that LRP4 protein is present in human and rodent osteoblasts and osteocytes, both presumed target cells of sclerostin action. Silencing of LRP4 by lentivirus-mediated shRNA delivery blocked sclerostin inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W and W1186S) in patients suffering from bone overgrowth. We found that these mutations impair LRP4 interaction with sclerostin and its concomitant sclerostin facilitator effect. Together these data indicate that the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone.

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Local communication on and within bone controls bone remodeling

Cited by 247 publications

References 138 publications

MicroRNAs as regulators of bone homeostasis and bone metastasis

MicroRNAs as regulators of bone homeostasis and bone metastasis

The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

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