Orthopaedic applications of gene therapy

Gene therapy presents a novel approach to biological treatment. Several orthopaedic diseases can cause changes in biological signalling at the tissue level that potentially can be repaired or modified by inserting genes into the cells or tissues to modulate gene expression. Impaired bone healing, need for extensive bone formation, cartilage repair and metabolic bone diseases are all conditions where alterations of the signalling peptides involved may provide cure or improvement. In orthopaedic oncology, gene therapy may achieve induction of tumour necrosis and increased tumour sensitivity to chemotherapy. In the last decade, extensive improvements have been made to optimise gene therapy and have been tested on several orthopaedic conditions. How far this development has come in orthopaedics is highlighted in this paper.

---

Résumé La thérapie génique représente une nouvelle approche comme traitement biologique. Plusieurs maladies orthopédiques peuvent causer des changements au niveau des tissus qui potentiellement peuvent être réparés ou modifiés en insérant des gènes dans les cellules pour moduler lexpression du gène. Les maladies métaboliques sont des conditions ou laltération de certains peptides particuliers peuvent fournir une guérison ou une amélioration. En oncologie la thérapie gènique peut améliorer la nécrose tumorale et accroitre la sensibilité de la tumeur à la chimiothérapie. Des améliorations importantes ont été faites dans la dernière décennie pour optimiser cette thérapie qui a été testée dans plusieurs conditions orthopédiques. Cet article envisage les développements actuels.

---

     

Erythropoietin in sports: a new look at an old problem

Erythropoietin (EPO) is found naturally in the human body and has been commercially available as recombinant human EPO (rEPO) for almost 20 years. Although the positive benefits of rEPO cannot be denied for those who suffer from anemia, athletes have also used the drug as an ergogenic aid. It has replaced conventional "blood doping" as the drug of choice to improve performance in contests requiring aerobic potential. Testing for the drug in the past has proven difficult due to several factors. The similarities in structure and metabolism of EPO and rEPO allow those who choose to abuse rEPO to avoid detection. Due to the inherent danger of abusing rEPO and its analogues, the various governing bodies of international sports continue to improve testing methods for this illegal substance.     

Flexor tendon pulley reconstruction

Pulley reconstruction remains a challenging intellectual and technical exercise. When performed correctly, however, it can be a gratifying procedure that provides much improved function of the digit. As described in this article, there are many different techniques by which the pulley can be reconstructed. Each of these techniques has distinct advantages and disadvantages. The hand surgeon should be familiar with each of these techniques and the general principles of pulley reconstruction as laid out in this article. With this knowledge base, the treating surgeon is able to tailor the procedure performed to the exact anatomy and clinical situation of each patient. Although great strides have been made over the past half century, more clinical research is needed to determine the best technique, not just in the cadaver model, but also in the complex model of the living human hand.     

The future of flexor tendon surgery

Clinical outcomes following flexor tendon repair have made significant improvements in the last 50 years. In that time standard treatment has evolved from secondary grafting to primary repair with postoperative rehabilitation protocols. Unfortunately, excellent results are not yet attained universally following treatment. Improving understanding of tendon healing at the cellular, molecular, and genetic levels will likely enable surgeons to modulate the normal repair process. We now look toward biologic augmentation of flexor tendon repairs to address the problems of increasing tensile strength while reducing adhesion formation following injury and operative repair.     

BMP binding peptide: a BMP-2 enhancing factor deduced from the sequence of native bovine bone morphogenetic protein/non-collagenous protein.

Forty years ago, Marshall Urist described a partially purified extract of demineralized bone matrix which induced the formation of ectopic bone. This substance, bone morphogenetic protein/non-collagenous protein (BMP/NCP), was never purified to homogeneity but other investigators used similar starting materials to clone a number of recombinant BMPs. Urist recognized that his material probably contained the BMPs which had been cloned by others but always contended that it contained another, more potent, bone inducing material which differed significantly in its physical and chemical properties from the known BMPs. We have used Urist's protocol to isolate a protein that has the chemical and physical properties of Urist's "BMP". It is an 18.5 kD fragment of the bone matrix protein, SPP-24. This fragment contains the cystatin-like domain of SPP-24. We have located a 19 amino acid region which is similar to the TGF-beta/BMP-binding region of fetuin, a member of the cystatin family of protease inhibitors. A cyclic peptide, which we call BMP binding peptide (BBP) was generated using this sequence. The peptide avidly bound rhBMP-2 with a KD of 3 x 10(-5) M. When implanted alone in mouse muscle, the peptide frequently induced dystrophic calcification. When implanted with rhBMP-2, the peptide enhanced the osteogenic activity of the recombinant molecule. We hypothesize that Urist's "BMP" was a fragment of SPP-24 which influenced bone induction by binding to bone morphogenetic proteins. BBP may be clinically useful because of its effects on other bone-inducing substances.     

Dietary protein to support anabolism with resistance exercise in young men

Resistance exercise is fundamentally anabolic and as such stimulates the process of skeletal muscle protein synthesis (MPS) in an absolute sense and relative to skeletal muscle protein breakdown (MPB). However, the net effect of resistance exercise is to shift net protein balance (NPB = MPS - MPB) to a more positive value; however, in the absence of feeding NPB remains negative. Feeding stimulates MPS to an extent where NPB becomes positive, for a transient time. When combined, resistance exercise and feeding synergistically interact to result in NPB being greater than with feeding alone. This feeding- and exercise-induced stimulation of NPB is what, albeit slowly, results in muscle hypertrophy. With this rudimentary knowledge we are now at the point where we can manipulate variables within the system to see what impact these interventions have on the processes of MPS, MPB, and NPB and ultimately and perhaps most importantly, muscle hypertrophy and strength. We used established models of skeletal muscle amino acid turnover to examine how protein source (milk versus soy) acutely affects the processes of MPS and MPB after resistance exercise. Our findings revealed that even when balanced quantities of total protein and energy are consumed that milk proteins are more effective in stimulating amino acid uptake and net protein deposition in skeletal muscle after resistance exercise than are hydrolyzed soy proteins. Importantly, the finding of increased amino acid uptake would be independent of the differences in amino acid composition of the two proteins. We propose that the improved net protein deposition with milk protein consumption is also not due to differences in amino acid composition, but is due to a different pattern of amino acid delivery associated with milk versus hydrolyzed soy proteins. If our acute findings are accurate then we hypothesized that chronically the greater net protein deposition associated with milk protein consumption post-resistance exercise would eventually lead to greater net protein accretion (i.e., muscle fiber hypertrophy), over a longer time period. In young men completing 12 weeks of resistance training (5d/wk) we observed a tendency (P = 0.11) for greater gains in whole body lean mass and whole as greater muscle fiber hypertrophy with consumption of milk. While strength gains were not different between the soy and milk-supplemented groups we would argue that the true significance of a greater increase in lean mass that we observed with milk consumption may be more important in groups of persons with lower initial lean mass and strength such as the elderly.