When I was just 3 months old, I was diagnosed with fibular hemimelia, a rare genetic condition that affects about 1 in 50,000 people. It manifests itself as the lack of the fibula bone, a key structural bone in the lower leg that provides major stability in the ankle and knee.
Fibular hemimelia leads to a severe leg length discrepancy — which, in my case, would have amounted to over 6 inches without treatment. Prior to my time at Boston Children’s Hospital, the go-to cure was amputation — replacing my lower leg with a series of prostheses.
Luckily, at the time of my diagnosis, leg-lengthening surgeries were just being approved in the U.S. My parents couldn’t bear to part with my leg, so over the course of 18 years, I have undergone 13 procedures to combat my leg-length difference, starting at age 5. This early exposure to the medical field, coupled with encouragement from teachers, led to a passion for science.
Even before high school, I was taught by my surgeon about how bone is formed: osteoblasts are the cells that lay down new bone and osteoclasts are the cells that break down old bone in order to maintain healthy bone.
During an independent research course at high school, I followed my passions into the fields of biochemistry and medicine. Most recently, motivated by my experience with the healing process, I looked at how emotional stress affects bone accrual.
Our bodies cope with both physical and emotional stress with the release of chemicals. The largest group of steroids released in response to emotional stress, glucocorticoids, naturally rise and fall in the bloodstream over the day. Oddly enough, glucocorticoids also have a role in maturing pre-osteoblasts into functioning osteoblasts. But when their bloodstream concentrations are higher than normal, they have a negative effect on osteoblasts: they induce apoptosis, a form of controlled cellular death. This disrupts the fragile equilibrium between bone making and bone breaking. The unbalance leads to osteoporosis, or at the very least, a decrease in bone density.
Since the effects of glucocorticoids on bone accrual and osteoblast viability are already well defined, my study focused on finding a way to increase these cells’ viability when exposed to excessive glucocorticoid concentrations. Through a search, I found a paper that suggested that the phytochemical sulforaphane (SFP) reduces glucocorticoid-induced apoptosis in osteoblasts.
I did my own experimentation to optimize the protocol and test the reproducibility of the results. Here is what I found:
Clearly there is a difference between the cells on the left, exposed exclusively to dexamethasone, a potent glucocorticoid, and those pre-treated with SFP (p value=0.0027). The difference becomes even more shocking when you look just at apoptosis:
Here we see that SFP has actually eliminated apoptotic osteoblast death entirely (p=0.0082) at a concentration of 0.1 micro-molar. (I also used concentrations of 20 to 120 micro-molar, but these resulted in elevated rates of necrosis.)
With these data, I can confidently say that SFP, in certain concentrations, has a beneficial effect in preventing glucocorticoid-induced apoptosis in osteoblasts. While I wasn’t able to fully investigate the mechanism of the apoptosis, I have a hypothesis as to why SFP works in the way it does and why it may be a good remedy.
Often, apoptosis is activated in response to oxidative stress, which is the release of free radicals like electrons and oxidants into the cell. These trigger enzymes that degrade the cell’s DNA and membrane. Antioxidants can combat the oxidants’ effects, and it has been shown that the Nrf2 cellular pathway regulates antioxidant production. SFP acts as a precursor to the Nrf2 pathway, cleaving macromolecules to initiate the Nrf2 cellular response.
What’s probably most extraordinary is that SFP is extremely common, found in all cruciferous vegetables, like broccoli, Brussels sprouts and cabbage. In terms of application of this research, I believe it has huge implications for the pharmaceutical industry. Glucocorticoids, in addition to being natural stress steroids, are the most widely used treatment for inflammatory diseases such as rheumatoid arthritis and have even shown some usefulness in the treatment of cancer. Unfortunately, the number one side effect of oral glucocorticoids is osteoporosis. If SFP could be turned into a pharmaceutical and taken in conjunction with glucocorticoids, the positive effect could be extremely meaningful.
As I progress onward in my higher education, entering the University of St. Andrews this fall in Scotland to study biochemistry, I am excited for all the new opportunities the sciences hold for me. At the time of this article, I am working in a research facility at the UMass Medical School, studying genomic integrity in fruit flies. I hope to continue research such in genomics and molecular biology in the future.