The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2

Zou, Weiguo; Greenblatt, Matthew B.; Brady, Nicholas J.; Lotinun, Sutada; Zhai, Bo; Rivera, Heather de; Singh, Anju; Sun, Jun; Gygi, Steven P.; Baron, Roland; Glimcher, Laurie H.; Jones, Dennis

doi:10.1083/jcb.2024oia68

Cited by 17 publications

(19 citation statements)

References 16 publications

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“…It is believed that Runx2 is a specific osteoblast transcription factor, which plays essential roles in bone formation . agomiR‐130a up‐regulated Runx2 expression while antagomiR‐130a down‐regulated it (Figure C).…”

Section: Resultsmentioning

confidence: 99%

“…MiRNAs combined with target mRNA on sites of the 3′‐UTR to regulate the expression of target mRNA in post‐transcriptional manner. It is well known that Smurf2 can suppress the expression of Runx2 activity, a critical osteoblast‐specific transcription factor, which leads to decreasing in osteoblast formation . Several studies have clearly demonstrated that PPARγ is highly expressed in early stage of adipogenesis and plays a key role in adipocyte formation .…”

Section: Discussionmentioning

confidence: 99%

“…42 a critical osteoblast-specific transcription factor, which leads to decreasing in osteoblast formation. 39,40 Several studies have clearly demonstrated that PPARγ is highly expressed in early stage of adipogenesis and plays a key role in adipocyte formation. 44,45 We illustrated that miR-130a promotes osteogenesis of BMSC by eliminating the effect of Smurf2 and acts as a negative regulator of adipogenesis of BMSC by directly targeting PPARγ.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

et al. 2019

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Objectives With age, bone marrow mesenchymal stem cells (BMSC) have reduced ability of differentiating into osteoblasts but have increased ability of differentiating into adipocytes which leads to age‐related bone loss. MicroRNAs (miRNAs) play major roles in regulating BMSC differentiation. This paper explored the role of miRNAs in regulating BMSC differentiation swift fate in age‐related osteoporosis. Material and methods Mice and human BMSC were isolated from bone marrow, whose miR‐130a level was measured. The abilities of BMSC differentiate into osteoblast or fat cell under the transfected with agomiR‐130a or antagomiR‐130a were analysed by the level of ALP, osteocalcin, Runx2, osterix or peroxisome proliferator‐activated receptorγ (PPARγ), Fabp4. Related mechanism was verified via qT‐PCR, Western blotting (WB) and siRNA transfection. Animal phenotype intravenous injection with agomiR‐130a or agomiR‐NC was explored by Micro‐CT, immunochemistry and calcein double‐labelling. Results MiR‐130a was dramatically decreased in BMSC of advanced subjects. Overexpression of miR‐130a increased osteogenic differentiation of BMSC and attenuated adipogenic differentiation in BMSC, conversely, Inhibition of miR‐130a reduced osteogenic differentiation and facilitated lipid droplet formation. Consistently, overexpression of miR‐130a in elderly mice dropped off the bone loss. Furthermore, the protein levels of Smad regulatory factors 2 (Smurf2) and PPARγ were regulated by miR‐130a with an negative effect through directly combining the 3'UTR of Smurf2 and PPARγ. Conclusions The results indicated that miR‐130a promotes osteoblastic differentiation of BMSC by negatively regulating Smurf2 expression and suppresses adipogenic differentiation of BMSC by targeting the PPARγ, and supply a new target for clinical therapy of age‐related bone loss.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

et al. 2019

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“…The present results suggested that miR-135b-5p was highly expressed in the bone tissues of patients with OP compared with patients with osteoarthritis. Osteoblasts are responsible for the formation and mineralization of the skeleton (27), and play important roles in OP; therefore, research on osteoblasts has become an important topic for OP in in vitro research (28,29). The present study focused on the effects of miR-135b-5p on osteogenic differentiation and osteoblast proliferation.…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of miR‑135b‑5p in bone tissue of patients with osteoporosis and its role and mechanism in osteoporosis progression

et al. 2019

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Osteoporosis (OP) is an age-related bone disease occurring worldwide. Osteoporotic fracture is one of the leading causes of disability and death in elderly patients. MicroRNAs (miRNAs/miRs) are key molecular regulatory factors in bone remodeling processes. The present study investigated the expression and mechanism of miR-135b-5p in patients with osteoporosis. The present results suggested that miR-135b-5p was upregulated in bone tissue fragments of patients with osteoporosis compared with the control patients. MC3T3-E1 cells were used to perform osteogenic differentiation induction. Reverse transcription-quantitative PCR and western blot assay were used to detect the mRNA and protein expression levels of the osteogenic markers osteocalcin (OC), Osterix and alkaline phosphatase (ALP). A specific kit was used for detecting ALP activity. The present results indicated that the mRNA expression levels of OC, Osterix and ALP significantly increased on the 7 and 14th day after osteogenic differentiation induction compared with the control group. Protein expression levels of OC, Osterix and ALP also increased on the 7 and 14th day after induction. ALP assay showed that ALP activity was significantly increased on the 7 and 14th day after induction. In addition, the present study found that miR-135b-5p was downregulated in MC3T3-E1 cells 7 and 14 days after osteogenic differentiation induction. The results of TargetScan analysis and dual luciferase reporter gene assay indicated that runt-related transcription factor 2 (RUNX2) was a direct target gene of miR-135b-5p. RUNX2 was upregulated in MC3T3-E1 cells on the 7 and 14th day after induction. Moreover, the present study found that compared with the osteogenic differentiation induction group, miR-135b-5p mimic significantly decreased OC, Osterix and ALP expression, and reduced ALP activity in MC3T3-E1 cells. However, these reductions were reversed following overexpression of RUNX2. The present results showed that miR-135b-5p mimic significantly reduced cell viability in MC3T3-E1 cells and induced cell apoptosis, and these effects were significantly reversed following RUNX2 overexpression. In summary, the present results suggested that miR-135-5p participated in the occurrence and development of osteoporosis via inhibition of osteogenic differentiation and osteoblast growth by targeting RUNX2. The present study suggested a novel potential target that may faciliate the treatment of osteoporosis, and further study is required to examine this possibility.

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“…In a novel approach, unidentified pro-osteoblastic and prochondrogenic factors and pathways could be obtained by unbiased siRNA screens using marker genes and enzymes as screening readouts. Such efforts have been performed by the Glimcher laboratory (435). Here, a lentiviral-based shRNA library that targeted 1,500 genes was transduced into primary MSCs.…”

Section: B Activating Bone Cell-protective Pathwaysmentioning

confidence: 99%

Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy

Hartmann

Koenen

Schauer

et al. 2016

Physiological Reviews

191

174

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Cartilage and bone are severely affected by glucocorticoids (GCs), steroid hormones that are frequently used to treat inflammatory diseases. Major complications associated with long-term steroid therapy include impairment of cartilaginous bone growth and GC-induced osteoporosis. Particularly in arthritis, GC application can increase joint and bone damage. Contrarily, endogenous GC release supports cartilage and bone integrity. In the last decade, substantial progress in the understanding of the molecular mechanisms of GC action has been gained through genome-wide binding studies of the GC receptor. These genomic approaches have revolutionized our understanding of gene regulation by ligand-induced transcription factors in general. Furthermore, specific inactivation of GC signaling and the GC receptor in bone and cartilage cells of rodent models has enabled the cell-specific effects of GCs in normal tissue homeostasis, inflammatory bone diseases, and GC-induced osteoporosis to be dissected. In this review, we summarize the current view of GC action in cartilage and bone. We further discuss future research directions in the context of new concepts for optimized steroid therapies with less detrimental effects on bone.

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The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2

Cited by 17 publications

References 16 publications

MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

Abnormal expression of miR‑135b‑5p in bone tissue of patients with osteoporosis and its role and mechanism in osteoporosis progression

Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy

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