Lancet Feb 1999.
Just doing some belated due diligence. Researching AFTER investing-- I hate it when I do that. Anyway, I came across a review in Lancet that you and others may want to take a look at. Please do not hesitate to favor this thread with an evaluation of the science and potential market here.
Since the discovery, in the 1960s, that demineralised bone could induce bone formation in rabbit muscle, scientists have cloned the genes for about 15 structurally related osteogenic factors. These bone morphogenetic proteins (BMPs) are now being used clinically in orthopaedics, but their ability to regulate growth and tissue differentiation in diverse situations has also led to an investigation of their therapeutic use in osteoporosis, renal disease, and tissue engineering.
BMPs-members of the transforming-growth-factor-[small beta, Greek] superfamily-are involved in the regulation of the growth and differentiation of cartilage and bone in embryos. "BMPs, together with other cytokines and matrix components, induce a cascade of chemotaxis, migration, proliferation, and differentiation of mesenchymal stem cells", explains Hari Reddi (University of California, Davis, CA, USA). For example, BMP-4 signals bone morphogenesis and repair. But it also stimulates the biosynthesis of, and binds to components of, the extracellular matrix. "BMP binding, to collagen IV and heparin, for instance, may have a key role in directing bone development", says Reddi. Interaction between BMPs and heparin in the extracellular matrix probably regulates the vascular invasion of cartilage before osteogenesis begins, he continues, and matrix binding of BMPs may also regulate their release and protect them from proteolytic degradation.
Bone repair was the first therapeutic application of BMPs to be explored. In a multicentre clinical trial in 122 patients, the results of which were reported by Clayton Perry (Washington University, St Louis, MO, USA) in 1998, recombinant human BMP-7 (also known as osteogenic protein-1), in combination with a collagen matrix, was as effective as autologous bone grafting in the repair of tibial fracture non-unions with an average duration of 28 months after the initial damage.
Andrew Shimmin (Melbourne Orthopaedic Group, Australia) has also used BMP-7 in patients with various relcalcitrant orthopaedic problems, including non-union, revision arthroplasty, and bone defects (eg, from osteolysis or tumour resection). "Only three of 44 patients with more than 3 months' follow-up failed both radiological and clinical assessment", he says. "Considering that all these patients had already failed conventional orthopaedic treatments, the bone-forming response to BMP-7 is very encouraging."
For efficient bone formation, BMPs need a carrier-one that is biodegradable, strong, non-immunogenic, and resorbable. Collagen is one such carrier. In their studies, Perry and Shimmin used an osteoinductive combination of BMP-7 and type-I collagen (derived from bone), developed by Stryker Biotech (Boston, MA, USA). This mix has the consistency of wet sand when hydrated with saline. When used for bone regeneration, it stimulates adjacent bone cells to grow into, and eventually replace, the collagen scaffold, which is then resorbed, says Sam Yin of Stryker Biotech. "BMP-7 acts like a switch, triggering the cascade of cellular events necessary for bone repair", he says.
"The great thing about the BMP-7/collagen type-I mixture", adds Yin, "is that it stimulates the patient's own cells and provides the surgeon with a biological tool for orthopaedic repair". And the use of BMP-7 instead of a bone graft avoids donor-site pain and blood loss. "In animals, bone defects repaired with the BMP-7 mix are radiographically, histologically, and mechanically as good as normal bone." But, notes Shimmin, though fine for treating small areas, the "wet sand" mix is difficult to contain at the site of a large defect. An alternative mixture containing carboxymethylcellulose has the consistency of putty.
Other potential applications of BMPs related to bone include: bone restoration in total joint arthroplasty; spinal fusion-results of several animal experiments were reported at the annual meeting of the American Academy of Orthopaedic Surgeons (Anaheim, CA, USA; Feb 4-8); regeneration of craniofacial defects; and the treatment of osteoporosis.
But the activities of BMPs, and consequently their clinical uses, are not confined to bone. Gene-knockout experiments in mice show that BMP-7 is essential for kidney and eye development, BMP-2 for heart development, and BMP-4 for mesoderm induction. And transgenic overexpression of BMP-6 causes psoriasis. "BMPs have a pivotal role in heart, kidney, skin, eye, and tooth development", says Reddi. "Their therapeutic potential looks very exciting." Here again, BMP binding to matrix proteins may be crucial to the development of diverse tissues, "orienting BMPs in an optimal conformation to initiate and maintain epithelial-mesenchymal interactions".
(* Figure 1*) One non-bone-related use of BMPs that looks particularly promising is the use of BMP-7 in the treatment of renal failure. Researchers at the University of Zagreb (Croatia) have shown that intravenous BMP-7 can both prevent and reverse acute ischaemic or toxic renal failure in rats. Slobodan Vukicevic explains: "It improves glomerular filtration rate, minimises infarction and cell necrosis, and reduces apoptosis in the recovery phase." The Zagreb team also found that BMP-7 delays or halts the progression of chronic renal failure in rats. "We are optimistic that BMP-7 will be beneficial clinically in renal failure", adds Vukicevic. |
