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Abstract Number: 5

Adalimumab Inhibits TNF-Enhanced Human Osteoclast Development More Effectively Than Other Biologic Agents Under in Vitro Conditions of Chronic TNF Exposure

Bohdan P. Harvey1 and Zehra Kaymakcalan2, 1Biologics, Abbott Laboratories, Worcester, MA, 2Biologics, Abbott, Worcester, MA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Abatacept, Adalimumab, etanercept, osteoclastogenesis and tumor necrosis factor (TNF)

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Session Information

Title: Biology and Pathology of Bone and Joint

Session Type: Abstract Submissions (ACR)

Background/Purpose: TNF-alpha (TNFa) has been shown to contribute to osteoclastogenesis independently and in conjunction with M-CSF or RANKL, two key cytokines involved in osteoclast development.  Both TNFa and RANKL have been concomitantly detected in the synovial fluid of RA patients.  However, the role of TNFa in promoting human osteoclast differentiation and activity in the presence of RANKL is poorly understood.  In this study, we sought to determine the impact of TNFa on RANKL-induced human osteoclast development and function under chronic conditions and to assess the effectiveness of various biologic agents in blocking the effect of TNF in this system.

Methods: Primary human osteoclast precursors (OCP) were exposed to various combinations of M-CSF, RANKL and TNFa (100 ng/mL) +/- increasing concentrations of adalimumab, etanercept or abatacept for up to 7 days.  Prior to adding to the cells, the biologics were pre-incubated with the cytokine cocktail for 30 min.  Osteoclast differentiation was determined by the presence of large multinucleated cells positive for tartrate-resistant acid phosphatase (TRAP) and by TRAP5b activity.  Resorptive activity was assessed by measuring the release of either the degradation products of plate-bound Europium-labeled collagen (Eu-col) or the cross-linked C-telopeptide of type I collagen (CTX-I) from human bone chips.

Results: In the absence of biologics, the addition of TNFa to OCP cultures with exogenous RANKL promoted earlier differentiation (increased TRAcP5b activity by day 4) and enhanced osteoclast activity (increased CTX-I levels by day 7) compared to RANKL alone.  Based on early time course assessments using Eu-col, TNFa enhanced the kinetics of osteoclast maturation by 13 hrs and maintained 3-fold higher levels of osteoclast activity for up to 122 hrs. Among the biologics, adalimumab restored the rate of osteoclast differentiation and activity to levels comparable to RANKL alone at concentrations 10-fold lower than etanercept (0.74 µg/mL and 20 µg/mL, respectively). Moreover, etanercept was unable to maintain its inhibitory effect even at the highest dose tested, while abatacept was ineffective in preventing TNF-mediated augmentation of osteoclast development at all concentrations tested. Interestingly, the levels of many TNFa-responsive pro-osteoclastogenic chemokines were similarly reduced in the presence of either adalimumab or etanercept, suggesting that both agents were able to neutralize TNF during early osteoclast development.

Conclusion: These findings demonstrate that TNFa can significantly enhance the kinetics of RANKL-induced osteoclast differentiation and activity.  Moreover, under chronic in vitro exposure of OCP to TNF, adalimumab is more effective than etanercept (or abatacept) in mitigating the pro-osteoclastogenic effects of TNF.  Overall, our results demonstrate the central role of TNF in RA joint destruction and the sustained potency of adalimumab as compared to other biologics in preventing bone erosion due to chronic TNF exposure.


Disclosure:

B. P. Harvey,

Abbott Laboratories,

3;

Z. Kaymakcalan,

Abbott Laboratories,

3.

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