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

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.

Accelerated tooth movement in Rsk2-deficient mice with impaired cementum formation

Coffin–Lowry–Syndrome(CLS)is a X-linked mental retardation characterized by skeletal dysplasia and premature tooth loss.We and others have previously demonstrated that the ribosomal S6 kinase RSK2,mutated in CLS,is essential for bone and cementum formation;however,it remains to be established whether RSK2 plays also a role in mechanically induced bone remodeling during orthodontic tooth movement(OTM).We,therefore,performed OTM in wild-type(WT)mice and Rsk2-deficient mice using Nitinol tension springs that were fixed between the upper left molars and the incisors.The untreated contralateral molars served as internal controls.After 12 days of OTM,the jaws were removed and examined by micro-computed tomography(μCT),decalcified histology,and immunohistochemistry.Our analysis of the untreated teeth confirmed that the periodontal phenotype of Rsk2-deficient mice is characterized by alveolar bone loss and hypoplasia of root cementum.Quantification of OTM usingμCT revealed that OTM was more than two-fold faster in Rsk2-deficient mice as compared to WT.We also observed that OTM caused alveolar bone loss and root resorptions in WT and Rsk2-deficient mice.However,quantification of these orthodontic side effects revealed no differences between WT and Rsk2-deficient mice.Taken together,Rsk2 loss-of-function accelerates OTM in mice without causing more side effects.