May 2004, Issue 2

An Experimentally Derived Model of Parathyroid Hormone—Receptor Binding

Michael Rosenblatt, MD, the new dean (November 2003) of Tufts University School of Medicine, could easily be thought of as a hard-core biochemist because of the research he does on the structural biology of hormone-receptor interactions. But he thinks of himself more as a physician/scientist interested in translational work connected to the needs of patients.

Rosenblatt's career attests to this belief. Not long after graduating from Harvard Medical School in 1973, and training in endocrinology at Massachusetts General Hospital, Rosenblatt started working at Merck, where he co-lead the pharmaceutical company's worldwide development team for the osteoporosis drug Fosamax. Eight years later he was back at Harvard, this time as a professor of medicine directing the Harvard-MIT Division of Health Sciences and Technology, training MDs, PhDs, and MD/PhDs. He served as president of Beth Israel Deaconess Medical Center from 1999 until 2001, and then took a sabbatical at Robert Weinberg's laboratory at the Whitehead Institute at MIT.

Rosenblatt's laboratory at Tufts is located on the 7th floor of the Jaharis Building but will be moving this summer into renovated space in the South Cove Building. Most of the postdocs and some of the faculty who worked with Rosenblatt in his laboratories at Beth Israel Deaconess Medical Center and Harvard Medical School have joined him at Tufts.

Rosenblatt has two main research interests a long-standing interest in the structural biology of hormone-receptor interactions in the parathyroid hormone field, and a more recent interest in the mechanisms of cancer metastasis to bone. Parathyroid hormone plays a critical role in the regulation of calcium levels in the blood. One way the hormone increases blood calcium is by activating mechanisms that draw the mineral from bone. Parathyroid hormone binds to and activates the same G-protein-coupled cell membrane receptor in its two major tissue sites of activity, bone and kidney. This activation causes the receptor to generate intracellular second messengers that are the hormone's causative agents. The ability to up- or down-regulate the actions of parathyroid hormone could help patients with hyperparathyroidism, wherein an excess of the hormone causes so much calcium removal from bone that bone density is severely impaired.

A bit of serendipity led to a medical use for parathyroid hormone about 30 years ago. Rosenblatt explains: "Two researchers in the UK, John Parsons and Jonathan Reeves, wanted to study the effects of parathyroid hormone when administered exogenously to animals, but the hormone was very hard to come by, so they only gave the animals little bits at a time. And, low and behold, these animals got more bone instead of less bone."

What those researchers discovered was that although parathyroid hormone causes bone loss when administered continuously in fairly high doses, it causes bone growth when injected in very small doses once a day. The mechanisms are still not clear, but we know that parathyroid hormone acts on bone-forming osteoblast cells.

"So with that kind of physiological, pathophysiological, and medicinal application background, we've been very interested in understanding how parathyroid hormone expresses its biological activity," Rosenblatt says. Besides wanting to understand the molecular basis of recognition, Rosenblatt is also interested in designing analogs of parathyroid hormone that might have different properties from the natural hormone. For example, an analog with greater potency for bone building would have a therapeutic use in osteoporosis. Conversely, a parathyroid hormone antagonist could compete for binding and block access to the receptor in cases where there's an excess of hormone.

Rosenblatt says that the most exciting thing his group has been doing is what they've been working on over the past decade experimentally mapping the parathyroid hormone-receptor complex. "We take analogs of parathyroid hormone and drape onto them a [photo-activatable] chemical entity that can crosslink to the receptor," he says. The hormone-receptor complex can then be isolated and fragmented to identify the hormone-receptor contact points. Repeat this process multiple times, and include NMR and computer-assisted molecular modeling in your experimental protocol, and you can build up a topographic map of the contact points of the hormone and the receptor. "And that means that we can begin to really start rationally designing these analogs, because we know what areas of the hormone-receptor interaction are important for binding the receptor, what areas are important for activating the receptor, and I think we now have a whole new way into the problem."

Rosenblatt's second major research interest, cancer metastasis to bone, developed when he was on sabbatical at the Whitehead Institute. "Robert Weinberg is one of the world's experts in breast cancer, and I'm kind of a bone guy. I was interested in the problem of why do certain cancers spread to bone." From the hundred or so kinds of cancer that affect humans, only five have high rates of metastasizing to bone - breast, prostate, thyroid, lung, and kidney cancers. "And when they're in bone, they cause lots of problems - pain, hypercalcemia, eventually death. People don't die of the primary. They die of the metastases," Rosenblatt explained. In a bold and risky move, he worked with then-postdoc Charlotte Kuperwasser to create an animal model of metastasis using human breast cancer cells and human bone as a target tissue. Rosenblatt "was not at all sure that it would work." It did.

His group now plans to grow enough of these metastatic colonies of human breast cancer to do DNA microarray transcriptional profiling and compare genes that are up- and down-regulated in metastases with those in the primary breast cancer tissue from which they came. "Then there are all kinds of experiments you could do. You could knock out the gene to see if you changed the phenotype to see if it no longer spreads. Or you could take that gene, put it into a cancer that doesn't metastasize to bone, and see if you could confer the phenotype."

Taking the bull by the horns to get to know his Tufts associates, and possible collaborators, Rosenblatt has set aside every other weekly lab meeting for an invited researcher to talk about his or her work. This plan has already yielded results. Rosenblatt is exploring collaborations with Dan Jay of the Physiology Department and with David Kaplan of the School of Engineering. Jake Chen, of the School of Dental Medicine and the Sackler Program in Cell, Molecular, and Developmental Biology, is also a likely collaborator, in light of his work on bone sialoprotein and cancer metastasis to bone. Rosenblatt is certainly matching actions with words, working to "create stronger partnerships in research and education across the university and with our affiliated hospitals."

For more information go to:

http://www.tufts.edu/sackler/physiology/faculty/rosenblatt/

http://www.tufts.edu/sackler/facultyIntros/rosenblattM.html

 

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