Negative regulation of osteoclast precursor differentiation by CD11b and ß2 integrin-B-cell lymphoma 6 signaling.

Negative regulation of osteoclastogenesis is important for bone homeostasis and prevention of excessive bone resorption in inflammatory and other diseases. Mechanisms that directly suppress osteoclastogenesis are not well understood. In this study we investigated regulation of osteoclast differentiation by the ß2 integrin CD11b/CD18 that is expressed on myeloid lineage osteoclast precursors. CD11b-deficient mice exhibited decreased bone mass that was associated with increased osteoclast numbers and decreased bone formation. Accordingly, CD11b and ß2 integrin signaling suppressed osteoclast differentiation by preventing receptor activator of NF-κB ligand (RANKL)-induced induction of the master regulator of osteoclastogenesis nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and of downstream osteoclast-related NFATc1 target genes. CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation of RANK expression and induction of recruitment of the transcriptional repressor B-cell lymphoma 6 (BCL6) to the NFATC1 gene. These findings identify CD11b as a negative regulator of the earliest stages of osteoclast differentiation, and provide an inducible mechanism by which environmental cues suppress osteoclastogenesis by activating a transcriptional repressor that makes genes refractory to osteoclastogenic signaling.

The post-NSAID era: what to use now for the pharmacologic treatment of pain and inflammation in osteoarthritis.

Traditionally, clinicians have relied heavily on the use of NSAIDs to treat the pain of osteoarthritis, as numerous studies have proven these agents effective. However, controversy has arisen regarding their use as first-line therapy, due to increasing awareness of their cardiovascular risks. One of these agents, rofecoxib, was withdrawn from the market in 2004 due to these concerns. Since that time, numerous studies have illustrated that many of the NSAIDs, both the selective cyclooxygenase-2 inhibitors and the traditional nonselective agents, may confer similar risks of cardiovascular toxicity. Although these agents may still be useful in many patients, concerns over side effects have begun to limit their use, and patients and clinicians are reaching for alternate agents. This review highlights the evidence behind the effectiveness of other, non-NSAID pharmacologic options in the treatment of pain and inflammation in osteoarthritis.