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New research by the Drakesmith group and collaborators shows that BMP inhibitors are able to reverse the main untreatable symptom of the disease.

Scanning electron micrograph of bone, computer-coloured blue. © David Gregory & Debbie Marshall CC BY 4.0

The research, led by Dr Sarah Gooding, is an equal collaboration between the groups of Prof Hal Drakesmith at the MRC Human Immunology Unit (RDM) and the group of Prof Claire Edwards at NDORMS and the Nuffield Department of Surgical Sciences.

 

Untreatable symptom

Multiple myeloma is an incurable bone marrow cancer that affects terminally differentiated plasma cells (mature B cells).  Patients with myeloma suffer from bone pain, fractures and osteoporosis. These symptoms can be managed and limited, but not reverted.

Bone damage result from the cancer’s ability to manipulate the bone marrow environment. In a healthy individual, a delicate equilibrium exists between osteoclasts and osteoblasts. Osteoclasts are able to break down bone as part of healthy bone development and healing. Osteoblasts have the opposite function, and are activated when new bone is required. The fine balance between these two activities allows for bone mass to be maintained, whilst allowing for plasticity.

In myeloma patients, the resulting inflammatory environment disrupts this delicate balance, leading to excessive osteoclast activity and reduced osteoblast function. Current treatments are able to limit, but not reverse, this bone damage.

 

New therapeutic target

Comparing the gene expression profile of bone-lining cells from myeloma-bearing versus healthy mice, the team showed that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitors, the cells that differentiate into osteoblasts. Using BMP signalling inhibitors, the team investigated whether blocking this signalling pathway could have a beneficial effect on bone loss. The researchers found that BMP signalling inhibition not only inhibited osteoclast activity (preventing further bone loss) but was also able to activate osteoblasts, restoring bone mass. The paper also describes the mechanism by which BMP signalling inhibition may have these positive effects.

"Although we have medicines in the clinic that inhibit osteoclast activity, and drugs such as anti-sclerostin antibodies which activate osteoblasts are in trial, there are no current therapies which have both these activities, as has been shown to be the case with BMP inhibitors here." said Dr Sarah Gooding "Such a therapy could have powerful bone-building potential, which is needed in the devastating bone damage caused by myeloma. However, the safety of such an approach in the context of cancers needs further investigation."

The paper was published in Nature Communications.

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