Horse Sense

When orthopedists think of the biology of bone formation and remodeling, they think protein and protein signaling. They might slap platelet-rich plasma into a bone defect, insert a collagen matrix to help recruit proteins to a site of disease or injury, or for an added punch add a protein-containing matrix such as Wyeth's BMP bone graft material Infuse.

Sugar molecules have long been suspected of also playing a role in the process of bone mineralization, but there's been much less emphasis on research elucidating their role. A group at Cambridge University, however, has recently shown that the same complex sugars found in abundance in cartilage and other connective tissues may play an important regulatory role in the bone mineralization process. I’d meant to follow up on this pretty obscure paper, which appeared in late September in the American Chemical Society's Chemistry of Materials, and was reminded to do so last week when I saw kids dressed in skeleton costumes for Halloween.

Dave Reid, who led the research, explains that many of the attempts to culture and synthesize biomimetic materials are based around assumptions that collagen and proteins both direct the formation of bone mineral and, importantly, stabilize bone mineral once it is formed, preventing runaway crystalization and growth.

Reid recently joined Melinda Duer’s group at Cambridge University. Duer is an NMR expert and has with a long-standing interest in studying equine diseases. She had the idea to use NMR to look at how the organic matrix promotes bone mineralization.

So Reid did just that, using readily available horse bones.

When he compared NMR scans of bone with those of equine cartilage, he saw similarities in the signatures in both. “We realized that the best explanation for the signal was if these molecules were proteoglycans and glycosaminoglycans [GAGs],” he says, suggesting that these carbs -- yes, the same stuff that goes into many popular nutritional supplements sold as joint remedies – could play a significant role in bone diseases where the amount or quality of the mineral is compromised. “I don’t think anyone has made the association between the complex sugars and the potential that association has for changing the way we think about how bone mineralizes, how it is formed, and its stability,” he adds.

Families with genetic defects in GAG and minor glycan metabolism leading to connective tissue disorders also have bone malformations, Reid points out. “It leads one to wonder if the deficiencies in GAG metabolism are translating into defects in bone metabolism at the molecular level.”

Admittedly, such defects are rare. But using genomics to study inherited defects in glycan metabolism and defects in the enzymes responsible for assembling GAGs at specific anatomic locations could lead to the identification of new drug targets outside the realm of the signaling and structural proteins now associated with bone disease.

A logical next step is to do more definitive chemical analysis using mass spec. Combining that with a genomics study of families with inherited bone disorders could lead to a gene target specific to GAG's role in bone mineralization, and IP.

It's still a long shot, but it makes horse sense.