An Integrative Approach to Bone Biology and Disease: Q&A With Fanxin Long, PhD

Editor's Note: The American Society for Bone and Mineral Research(ASBMR) honored Fanxin Long, PhD, at the ASBMR 2023 Annual Meeting in Vancouver with the Louis V. Avioli Founders Award. One of the society’s most prestigious awards, it honors an ASBMR member for fundamental contributions to bone and mineral basic research and significant contributions to the field. Dr. Long is the William Wikoff Smith Endowed Chair in Pediatric Genomic Research at Children’s Hospital of Philadelphia.

What does the Louis V. Avioli Founders Award represent to you?

Receiving the award was quite an honor as it is considered the highest honor in the ASMBR for basic research. The fact that the award is named after Dr. Avioli, a prominent researcher and visionary leader in the field, is doubly special for me, as I started my career in the division he created.

Bone and mineral research was historically situated under endocrinology since the hormones in the body regulate bone and mineral density. Dr. Avioli realized the great effects that problems of the skeleton place on human health and founded a separate Division of Bone and Mineral Diseases at Washington University School of Medicine in St. Louis.

What led you to choose a focus in skeletal development and disorders?

My initial fascination with the skeleton was its diverse form, shape, and size among mammals. The reason we look different from the chimpanzee is partly because of the different skeletons. Bats’ wings are the equivalent of our hands, only with the digits enormously elongated. The skeleton as a structure sparked my curiosity about skeletal biology.

Skeletal health is important for reasons that are not always obvious. One of the fundamental functions of the skeleton is to be a reservoir for minerals such as calcium and phosphorus that are only released when needed. For example, during pregnancy, hormones tell the skeleton to release calcium so that nutrient is available for the developing fetus. In addition, there are many diseases that originate in the bone marrow. 

What is most exciting about how science has evolved in your field over time?

We have come far in terms of technology. Science moves very fast, and yet fundamental questions remain the same: How do the diseases occur? What are we going to do about it? The way to address these questions in Dr. Avioli’s day was to look at organs, tissues, and cells, but there was only limited understanding of the genes and molecules involved in regulating their function.

Now, the whole field has moved heavily into molecular and genetic research, which provides a fundamental understanding of skeletal cell formation and malformation. More importantly, the development of sophisticated approaches in genomics, proteomics, and metabolomics enables a global view of the entire genome and all the metabolites in the cell.

This allows us to compare normal conditions versus disease conditions, helping us to focus on areas of importance, such as a gene we’ve yet to study. This unbiased omics and global approach to the genome and transcriptome is a major transformation for the field.

What is the current focus of your work?

A major part of our research is understanding the causes for bone loss as seen in osteopenia or osteoporosis. While that mostly affects people of advancing age, it also has implications in children, who may have congenital osteoporosis or secondary bone loss from therapies necessary for treating other diseases. Glucocorticoid steroids, for example, are used to fight inflammation but are also notorious for weakening the bones. Common diseases such as diabetes are also known to cause bone loss. Our research is focused on how to mitigate bone loss caused by either primary diseases or secondary complications from necessary medicines. We are particularly interested in the possibility of boosting energy metabolism in bone cells to build more bone.

We also are interested in a better understanding of the role of stem cells in bone health. We are studying implications of the bone stem cells residing in the marrow, which tend to become fat in humans as we age. Stem cells also are found on the surface of the bone. These stem cells are most abundant in young children whose bones are not only growing longer, but wider.

Once our bodies have grown and matured, those stem cells remain important for supporting the normal turnover of bone, but they become most active when you fracture a bone as they are critical to the healing process. Through greater understanding of the molecular and metabolomic processes that convert stem cells into bone cells, we aim to develop a therapy to recover or restore lost bone.

What do you think is next for your field in the next five years and in the long term?

The future of skeletal biology lies in researching all the different complexity levels of bone biology through interdisciplinary collaboration. Asking questions across disciplines to gain understanding from the organismal level down to the gene regulation level will provide a comprehensive view of the genesis of bone disease and help us arrive at new therapies. This is, in fact, the motivation behind the newly created Skeletal Health and Diseases Research Affinity Group at CHOP. I envision that progress in the field in the next number of years will be both deep and wide. In terms of depth, the rapidly evolving single cell omics and spatial omics technologies will bring unprecedented resolution to the cellular composition and organization of the skeleton. On the other hand, integrative research is expected to broaden our view on how the skeleton communicates with other organs of the body, either through secreted proteins or perhaps metabolic products in the circulation.