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Methotrexate May Mitigate Inflammatory Bone Disease Note Experts at the ACR/ARHP Winter Rheumatology Symposium

Kimberly Retzlaff  |  Issue: April 2014  |  April 2, 2014

In established inflammatory bone disease, there is an increase in osteoclasts, B cells, T cells and TNF. These cytokines and other inflammatory cytokines have been shown to contribute to inflammation in RA and other inflammatory diseases, Dr. Cronstein said.

During osteoclast differentiation, one receptor that is particularly noteworthy is receptor activator of nuclear factor–κB (RANK) and RANK-ligand (RANKL).

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“[Osteoclasts] express this receptor called RANK and [RANKL], which is a protein that’s expressed on the surface of osteoblasts, and there’s also a soluble form,” Dr. Cronstein said. “This is one very well worked out way that osteoblasts talk to osteoclasts. Either the RANKL on the surface of osteoblasts or the soluble form binds to the receptor on the osteoclast precursors, and that induces differentiation to form osteoclasts.”

Of note, RANKL antibodies can be used to inhibit bone turnover and treat very severe forms of OA, Dr. Cronstein said.

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In addition to RANK and RANKL, the communication between osteoblasts and osteoclasts involves several other molecules, including Sema4D–plexin-B1 and TGF-β1. “Sema4D is a molecule made by osteoclasts that turns off osteoblasts, and there are many other molecules that have similar types of functions.” One such molecule, TGF-β1, is one of the basic growth factors that’s suppressed in the body and is required for growth of many different kinds of tissues.

By regulating the molecules that promote or inhibit osteoclast/osteoblast processes (e.g., differentiation, communication), it’s possible to mediate bone loss.

Adenosine & Methotrexate

Another key component of bone homeostasis is adenosine, which contributes to intercellular communication via its four receptors. Of note, “the antiinflammatory effects of methotrexate are largely mediated by adenosine,” Dr. Cronstein said. “Adenosine, acting at its receptors, inhibits bony destruction in inflammatory arthritis.”

Further, he said, stimulating adenosine A2A receptors is known to inhibit osteoclast differentiation, whereas deletion of A2A receptors leads to increased osteoclasts and diminished bone density. The antiinflammatory effects of methotrexate related to inflammatory bone disease are mediated by adenosine in the following ways:

  • Antagonism of A1 prevents osteoclast formation and function.
  • Stimulation of A2A prevents osteoclast formation and function.
  • Stimulation of A2B is critical for osteoblast differentiation.

“Bone destruction is mediated by the same cells that are normally present, you just get an exaggeration of the turnover component during inflammatory disease such as RA,” Dr. Cronstein said. “With methotrexate, adenosine can inhibit inflammation and bone destruction, and we’ve shown in models of inflammatory arthritis that methotrexate, working through adenosine, can inhibit the bone destruction that occurs.”

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Filed under:ConditionsDrug UpdatesMeeting ReportsOsteoarthritis and Bone DisordersOther Rheumatic ConditionsRheumatoid Arthritis Tagged with:ACR/ARHPAdenosineanti-inflammatorybonedrugMethotrexateOsteoarthritispatient careRheumatoid arthritisrheumatologist

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