RabGAP TBC1D25 is involved in human osteoclast activity

Bacterial infection in orthopedic surgery is challenging because cell wall components released after bactericidal treatment can alter osteoblast and osteoclast activity and impair fracture stability. However, the precise effects and mechanisms whereby cell wall components impair bone healing are unclear. In this study, we characterized the effects of lipopolysaccharide (LPS) on bone healing and osteoclast and osteoblast activity in vitro and in vivo and evaluated the effects of ibudilast, an antagonist of toll-like receptor 4 (TLR4), on LPS-induced changes. In particular, micro-computed tomography was used to reconstruct femoral morphology and analyze callus bone content in a femoral defect mouse model. In the sham-treated group, significant bone bridge and cancellous bone formation were observed after surgery, however, LPS treatment delayed bone bridge and cancellous bone formation. LPS inhibited osteogenic factor-induced MC3T3-E1 cell differentiation, alkaline phosphatase (ALP) levels, calcium deposition, and osteopontin secretion and increased the activity of osteoclast-associated molecules, including cathepsin K and tartrate-resistant acid phosphatase in vitro. Finally, ibudilast blocked the LPS-induced inhibition of osteoblast activation and activation of osteoclast in vitro and attenuated LPS-induced delayed callus bone formation in vivo. Our results provide a basis for the development of a novel strategy for the treatment of bone infection.

Download Full-text

SAT0161 Menatetrenone acts directly on circulating human osteoclast precursors

10.1136/annrheumdis-2001.648 ◽

2001 ◽

Author(s):

T Hirayama ◽

H Taira ◽

O Kudo ◽

I Itonaga ◽

T Torisu ◽

...

Keyword(s):

Osteoclast Precursors ◽

Human Osteoclast

Download Full-text

Dietary Salt Accelerates Orthodontic Tooth Movement by Increased Osteoclast Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22020596 ◽

2021 ◽

Vol 22 (2) ◽

pp. 596

Author(s):

Agnes Schröder ◽

Joshua Gubernator ◽

Alexandra Leikam ◽

Ute Nazet ◽

Fabian Cieplik ◽

...

Keyword(s):

Bone Density ◽

Bone Loss ◽

Bone Metabolism ◽

Tooth Movement ◽

Orthodontic Tooth Movement ◽

Dietary Salt ◽

Osteoclast Activity ◽

Salt Uptake ◽

Periodontal Bone Loss ◽

The Impact

Dietary salt uptake and inflammation promote sodium accumulation in tissues, thereby modulating cells like macrophages and fibroblasts. Previous studies showed salt effects on periodontal ligament fibroblasts and on bone metabolism by expression of nuclear factor of activated T-cells-5 (NFAT-5). Here, we investigated the impact of salt and NFAT-5 on osteoclast activity and orthodontic tooth movement (OTM). After treatment of osteoclasts without (NS) or with additional salt (HS), we analyzed gene expression and the release of tartrate-resistant acid phosphatase and calcium phosphate resorption. We kept wild-type mice and mice lacking NFAT-5 in myeloid cells either on a low, normal or high salt diet and inserted an elastic band between the first and second molar to induce OTM. We analyzed the expression of genes involved in bone metabolism, periodontal bone loss, OTM and bone density. Osteoclast activity was increased upon HS treatment. HS promoted periodontal bone loss and OTM and was associated with reduced bone density. Deletion of NFAT-5 led to increased osteoclast activity with NS, whereas we detected impaired OTM in mice. Dietary salt uptake seems to accelerate OTM and induce periodontal bone loss due to reduced bone density, which may be attributed to enhanced osteoclast activity. NFAT-5 influences this reaction to HS, as we detected impaired OTM and osteoclast activity upon deletion.

Download Full-text

TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-219262 ◽

2021 ◽

pp. annrheumdis-2020-219262

Author(s):

Cecilia Ansalone ◽

John Cole ◽

Sabarinadh Chilaka ◽

Flavia Sunzini ◽

Shatakshi Sood ◽

...

Keyword(s):

Epigenetic Modification ◽

Human Peripheral Blood ◽

Joint Destruction ◽

Receptor Expression ◽

Skeletal Health ◽

Flow Cytometric ◽

Human Osteoclast ◽

The Relationship ◽

Pathological Consequence ◽

Necrosis Factor

ObjectivesCirculating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood.MethodsFlow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy.ResultsTNF can act as a critical homoeostatic regulator of CD14+ monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14−CD16−CD11c+ myeloid pre-OC population was exempt from this negative regulation. In healthy CD14+ MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14+ MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis.ConclusionsThese findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway.

Download Full-text