Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator.

Cell transformation by Rous sarcoma virus results in a dramatic change of adhesion structures with the substratum. Adhesion plaques are replaced by dot-like attachment sites called podosomes. Podosomes are also found constitutively in motile nontransformed cells such as leukocytes, macrophages, and osteoclasts. They are represented by columnar arrays of actin which are perpendicular to the substratum and contain tubular invaginations of the plasma membrane. Given the similarity of these tubules to those generated by dynamin around a variety of membrane templates, we investigated whether dynamin is present at podosomes. Immunoreactivities for dynamin 2 and for the dynamin 2–binding protein endophilin 2 (SH3P8) were detected at podosomes of transformed cells and osteoclasts. Furthermore, GFP wild-type dynamin 2aa was targeted to podosomes. As shown by fluorescence recovery after photobleaching, GFP-dynamin 2aa and GFP-actin had a very rapid and similar turnover at podosomes. Expression of the GFP-dynamin 2aaG273D abolished podosomes while GFP-dynaminK44A was targeted to podosomes but delayed actin turnover. These data demonstrate a functional link between a member of the dynamin family and actin at attachment sites between cells and the substratum.

https://rupress.org/jcb/article-pdf/150/2/377/1293573/9912134.pdf

A Functional Link between Dynamin and the Actin Cytoskeleton at Podosomes

Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P, SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts.

/pdf/osteoblast-osteoclast-communication-and-bone-homeostasis-580yalq0a2.pdf

Osteoblast-Osteoclast Communication and Bone Homeostasis

https://mysite.science.uottawa.ca/rsmith43/bone.pdf

Mathematical model predicts a critical role for osteoclast autocrine regulation in the control of bone remodeling

Post‐transplantation bone disease: The role of immunosuppressive agents and the skeleton

The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that rediscovering a phenomenon that was first observed more half a century ago will have an important impact on our understanding of how new antifracture treatments work.

https://journals.sagepub.com/doi/pdf/10.1177/1759720X16670154

Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.

We have studied the effects of cyclosporine A (CsA) on basal and bovine parathyroid hormone (1-34) (bPTH)-stimulated bone resorption by osteoclasts in 24-hour cultures of chick long bone cells. At a high concentration (10 micrograms/ml), CsA had a cytotoxic effect on both osteoclasts and mononuclear cells in the culture. At 1 microgram/ml, CsA inhibited basal and bPTH-stimulated bone resorption but was not cytotoxic over 24 hours. We also studied the binding of bPTH to the osteoblastic cell line, Saos-2, and chick long bone cells in suspension culture. CsA inhibited bPTH binding in Saos-2 in a dose-dependent manner; inhibition of binding was also observed in chick bone cells. The effects of CsA on osteoclast viability and resorptive function may be due to a direct effect on the osteoclasts and/or to an interaction with the nonosteoclastic cell population in the culture.

https://link.springer.com/content/pdf/10.1007/BF02556217.pdf

David W. Dempster

Papers

Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.

Effects of cyclosporine A on chick osteoclasts in vitro.