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Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling.

ABSTRACT: Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1 (Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass. Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand (RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor (PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF-RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans.

SUBMITTER: Bartelt A

PROVIDER: S-EPMC5826921 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling.

Bartelt Alexander A Behler-Janbeck Friederike F Beil F Timo FT Koehne Till T Müller Brigitte B Schmidt Tobias T Heine Markus M Ochs Laura L Yilmaz Tayfun T Dietrich Martin M Tuckermann Jan P JP Amling Michael M Herz Joachim J Schinke Thorsten T Heeren Joerg J Niemeier Andreas A

Bone research 20180226

Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1 (Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and ...[more]

PMID: 29507818

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Project description:Osteoporosis deteriorates bone mass and biomechanical strength, becoming a life-threatening cause to the elderly. MicroRNA is known to regulate tissue remodeling; however, its role in the development of osteoporosis remains elusive. In this study, we uncovered that silencing miR-29a expression decreased mineralized matrix production in osteogenic cells, whereas osteoclast differentiation and pit formation were upregulated in bone marrow macrophages as co-incubated with the osteogenic cells in transwell plates. In vivo, decreased miR-29a expression occurred in ovariectomy-mediated osteoporotic skeletons. Mice overexpressing miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg/OCN) displayed higher bone mineral density, trabecular volume and mineral acquisition than wild-type mice. The estrogen deficiency-induced loss of bone mass, trabecular morphometry, mechanical properties, mineral accretion and osteogenesis of bone marrow mesenchymal cells were compromised in miR-29aTg/OCN mice. miR-29a overexpression also attenuated the estrogen loss-mediated excessive osteoclast surface histopathology, osteoclast formation of bone marrow macrophages, receptor activator nuclear factor-κ ligand (RANKL) and C-X-C motif chemokine ligand 12 (CXCL12) expression. Treatment with miR-29a precursor improved the ovariectomy-mediated skeletal deterioration and biomechanical property loss. Mechanistically, miR-29a inhibited RANKL secretion in osteoblasts through binding to 3'-UTR of RANKL. It also suppressed the histone acetyltransferase PCAF-mediated acetylation of lysine 27 in histone 3 (H3K27ac) and decreased the H3K27ac enrichment in CXCL12 promoters. Taken together, miR-29a signaling in osteogenic cells protects bone tissue from osteoporosis through repressing osteoclast regulators RANKL and CXCL12 to reduce osteoclastogenic differentiation. Arrays of analyses shed new light on the miR-29a regulation of crosstalk between osteogenic and osteoclastogenic cells. We also highlight that increasing miR-29a function in osteoblasts is beneficial for bone anabolism to fend off estrogen deficiency-induced excessive osteoclastic resorption and osteoporosis.

Dataset Information

Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling.

Publications

Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling.

Similar Datasets

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