Background/Purpose:

Claudins (Cldns) are well-established components of tight junctions (TJs) that play a pivotal role in the modulation of paracellular permeability. Several studies have explored the physiologic aspects of Cldn family members in bone metabolism. However, the effect of Cldn11, a major component of central nervous system myelin, on bone homeostasis has not been reported. this study was performed to identify the effects of Cldn on bone metabolism via regulation of osteoclast and osteoblast differentiation and their function

Methods:

We performed various in vitro and in vivo studies using gain- and loss-of function of Cldn11 that is belong to the Cldn group. Osteoclast formation from bone marrow cells (BMC) and Osteoblast formation was evaluated in specific condition with over-expression or down- regulation of Cldn11. The expression of osteoclast associated gene and osteoblast related gene mRNA were assessed by RT-PCR. The levels of c-fos and NFATc1 protein were assessed by western blot. Also the mitogen-activated protein (MAPK)s and important signal pathways were measured using Western blot analysis. Osteoclast function was evaluated with resorption pit assay and osteoblastic effects of Cldn11 was evaluated with new bone formation of mouse calvaria. With LPS and co-treated Recombinant protein of Cldn11 on mouse calvaria, we evaluated the effects of Cldn11 on LPS induced bone loss by using histologic analysis.

Results:

We found that Cldn11 played a negative role in receptor activator of nuclear factor kappa B ligand dependent osteoclast (OC) differentiation by downregulating the phosphorylated form of extracellular signal-regulated kinase (ERK), Bruton’s tyrosine kinase, and phospholipase C gamma 2, in turn impeding c-Fos and nuclear factor of activated T cells c1 expression. Osteoblast (OB) differentiation by positive feedback of Cldn11 was achieved through the phosphorylation of Smad1/5/8, ERK, and c-Jun amino-terminal kinase. Importantly, this Cldn11-dependent dual event arose from targeting EphrinB2 ligand reverse signaling into OC and EphB4 receptor forward signaling into OB. In agreement with these in vitro effects, subcutaneous injection of Cldn11 recombinant protein exerted similar effects on local calvarial regions in mice.

Conclusion:

These findings suggest that Cldn11 is a novel regulator in bone homeostasis.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/claudin-11-regulates-bone-homeostasis-via-bidirectional-ephb4-ephrinb2-signaling/