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A Cautionary Tale About Therapeutic Manipulation Of Bone Formation

In recent decades, there has been a significant increase in clinical efforts to develop bone anabolic agents that enhance bone regeneration by stimulating the activity of bone-forming cells, the osteoblasts. The therapeutic applications of many of bone anabolics available today including the parathyroid hormone-related protein (Tymlos®, Radius), the anti-Sclerostin antibody (Romosozumab®, Amgen), and Strontium Ranelate (Protelos®, Servier) were met with varying degrees of clinical success.

In 2012, an elegant study published in the scientific journal Nature identified Semaphorin 3A (Sema3A) as a new osteoblast-derived bone anabolic. Hayashi and colleagues demonstrated that Sema3A enhanced new bone formation and protected against bone loss in osteoporotic mice. Others studies that preceded and followed this report consolidated and expanded on these findings by showing that Sema3A plays a role in early development of the skeletal system and encourages fracture healing.

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Intrigued by these reports, we wondered whether Sema3A is functionally important for the behaviour of osteoblasts in cancer. To study this, we used a mouse model of osteosarcoma, a debilitating bone cancer. This approach allowed us to study the effects of Sema3A on the growth, differentiation and activity of both healthy and cancerous osteoblasts, with the latter being osteosarcoma cells. Using this model, we were also able to test if exposure to Sema3A affects the ability of osteosarcoma cells and healthy osteoblasts, both present in the tumor microenvironment, to produce disorganized and immature “woven” bone.

In our paper published in Scientific Reports, we have reported that exposure of healthy osteoblasts and human and mouse osteosarcoma cells to commercially-available Sema3A in the petri dish increased the ability of these cells to differentiate and to express some of the characteristics of mature osteoblasts. Most importantly, administration of Sema3A in mice increased bone volume in both healthy and osteosarcoma-bearing legs of mice. These effects were indicative of the bone protective effect of Sema3A, and are in broad agreement with the findings of the 2012 study by Hayashi and colleagues.

A surprising finding of our study was that mice injected with human osteosarcoma cells engineered to produce Sema3A had significantly less disorganized and immature “woven” bone. This effect was not observed in osteosarcoma-bearing mice injected with commercially-available Sema3A. Detailed functional and histological analysis of mouse bones indicated that exposure to tumor-derived Sema3A diminished the ability of osteosarcoma cells to produce woven, cancerous bone. Further mechanistic studies in cells in the petri dish revealed that sustained and prolonged exposure to tumor-derived Sema3A caused cells to produce a protein called DKK1, a potent inhibitor of bone formation.

When combined with previous studies, our latest results suggest that administration of commercially-available Sema3A increases the formation of new bone in health, but a sustained and prolonged exposure to tumor-derived Sema3A diminishes the ability of osteosarcoma cells to produce woven, cancerous bone. Thus, application of Sema3A — or synthetic agents that mimic its action — in osteosarcoma may provide a win-win therapeutic approach that enhances healthy bone regeneration and reduces the formation of cancerous bone.

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Writing in our paper, we also cautioned, “inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term usefulness as bone anabolic agent.” This is an educated guess based on our findings that showed that cells of the osteoblast lineage may react to a sustained overabundance of bone anabolics such as Sema3A by producing an inhibitor of bone formation. Therefore, the potential usefulness of Sema3A as a bone anabolic agent warrants further investigation.

These findings are described in the article entitled Bidirectional regulation of bone formation by exogenous and osteosarcoma-derived Sema3A, recently published in the journal Scientific Reports. This work was conducted by Daniëlle de Ridder, Silvia Marino, Ryan T. Bishop, and Aymen I. Idris from the University of Sheffield, in collaboration with Professor D. Heymann’s laboratory at the University of Nantes. This research was funded by the Bone Cancer Research Trust.

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