The Holy Grail for many orthopedic surgeons is the ability to rebuild or replace not only damaged joint cartilage but tissues, such as tendons and ligaments, that support the joints. Basic research in pursuit of this objective, by HHMI investigator David M. Kingsley of Stanford University School of Medicine and other scientists, often focuses on factors that control the formation of joints during embryonic development. "Everyone hopes that a better understanding of the process by which joints are originally built may in the long term help devise strategies for repairing joints that are damaged in adulthood," Kingsley says.
In a developing embryo, joint formation takes place largely within dense regions of cells called skeletal condensations, which develop first into cartilage and then into bones and joints. "Along the length of those skeletal condensations, at reproducible times and places during development, you'll see the beginnings of the segmentation process," which splits a bone-to-be into smaller pieces connected by joints, Kingsley explains. If this precisely orchestrated process is disrupted, bones and joints form abnormally.
Among the players in this process are members of a family of growth factors known as bone morphogenetic proteins (BMPs), which control many aspects of joint development by binding to specific cell-surface receptors and triggering a chain of signaling events within the cell. Kingsley and other developmental biologists have shown that mice with genetic defects in particular BMPs have abnormal cartilage and joint formation in different regions of the skeleton. Studies by HHMI investigator Matthew L. Warman, at Case Western Reserve University School of Medicine, and others show that mutations in some of these BMPs, and in factors that interact with BMPs, also cause a range of human hereditary disorders of limb and joint development.
In the developing mouse embryo, the gene for one BMP, called growth/differentiation factor 5 (Gdf5), "turns on in a beautiful pattern of stripes at all of the sites where joints are going to form," Kingsley says. "It's one of the strongest and earliest known markers for the joint-formation process." Two genes closely related to Gdf5 "also turn on in stripes, but only in some of the stripes," suggesting that BMPs can control formation of specific joints. Indeed, "when we've trawled through the [BMP] genes
we have found small stretches of DNA that will tell a gene to turn on in the elbow, but not in the finger," he says.
"We're interested not only in whether the BMP-signaling pathway plays an important role in stimulating early events of joint formation but also in whether it may be required for later stages of joint maintenance," Kingsley says.
Orthopedic researchers who are developing tissue-engineering techniques to repair damaged joints will also be interested in the results of ongoing studies on BMPs. In fact, Kingsley says, many scientists who spoke at the most recent international conference devoted to BMPs are already exploring the use of these growth factors to help transplanted articular cartilage cells heal cartilage defects. They're also looking at the effects of BMPs on tissues such as tendons and ligaments.
Elia T. Ben-Ari
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Reprinted from the HHMI Bulletin,
June 2003, pages 8-13.
©2003 Howard Hughes Medical Institute