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Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGf–RANKL signaling

Bone Research 2018年第1期6卷 50-59页

作者： Alexander Bartelt friederike Behler-Janbeck f.timo beil Till Koehne Brigitte Müller Tobias Schmidt Markus Heine Laura Ochs Tayfun Yilmaz Martin Dietrich Jan P.Tuckermann Michael Amling Joachim Herz Thorsten Schinke Joerg Heeren Andreas Niemeier Department of Orthopaedics University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Biochemistry and Molecular Cell Biology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Osteology and Biomechanics University Medical Center Hamburg-EppendorfMartinistr5220246 HamburgGermany Department of Orthodontics University Medical Center Hamburg-EppendorfMartinistr52 20246 HamburgGermany Department of Anatomy and Experimental Morphology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Molecular Genetics University of Texas Southwestern Medical CenterDallasTX 75390USA Institute for Comparative Molecular Endocrinology University of UlmUlmGermany Correspondence:Andreas Niemeier Department of Genetics and Complex Diseases&Sabriülker Center Harvard T.H.Chan School of Public Health665 Huntington AvenueBostonMA 02115USA

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 *** 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.

关键词： PDGfRβ RANKL activator receptor imatinib axis gene vivo

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Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： Laura J.Brylka Assil-Ramin Alimy Miriam E.A.Tschaffon-Müller Shan Jiang Tobias Malte Ballhause Anke Baranowsky Simon von Kroge Julian Delsmann Eva Pawlus Kian Eghbalian Klaus Püschel Astrid Schoppa Melanie Haffner-Luntzer David J.Beech frank timo beil Michael Amling Johannes Keller Anita Ignatius Timur A.Yorgan Tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal Medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and Metabolic Medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell *** we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in *** we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)*** with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate ***,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth *** skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of ***,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage ***,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) *** further observed increased Piezo1 protein abundance in cartilaginous zones of human ***,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in ***,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

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