Radovan Mihelic

Hip osteoarthritis susceptibility is associated with IL1B -511(G>A) and IL1 RN (VNTR) genotypic polymorphisms in Croatian Caucasian population

Among the predisposing factors to osteoarthritis (OA), a frequent destructive joint disease, is the complex genetic heritage including the interleukin‐1 family members like the IL1β (IL1B) and the IL1 receptor antagonist (IL1RN) genes. The aim of this study was to investigate allelic and genotypic frequencies of the IL1B gene single nucleotide polymorphism (SNP) at −511(G>A) and the variable number tandem repeat (VNTR) in the IL1RN gene in a Croatian Caucasian population of hip OA (HOA) cases and healthy controls. A total of 259 HOA patients with total hip replacement (THR) and 518 healthy blood donors as controls were genotyped for IL1B gene SNP −511(G>A) and the VNTR in the IL1RN gene associated with HOA. The genotype G/A (1/2) at IL1B was significantly associated with the protection of the HOA (p < 0.036, OR = 0.72, 95% CI = 0.52–0.99). The genotype G/G (1/1) had only a trend towards the susceptibility (p = 0.053, OR = 1.35, 95% CI = 0.98–1.86) to disease. None of the haplotypes IL1B −511(G>A) and IL1RN (VNTR) were found associated with the HOA. The haplotype 1–2 at these loci had only a trend to susceptibility (p = 0.065). Haplotype 1–3 had a significant male bias in diseased. Furthermore, genotype comprising 2–1/2–2 haplotypes was found significantly associated with predisposition to HOA (p = 0.027, OR = 2.23, 95% CI = 1.03–4.88), whereas genotype 1–1/2–2 with protection to disease (p = 0.028, OR = 0.65, 95% CI = 0.43–0.97). Our findings suggest that HOA in Croatian population might have a different genetic risk regarding the IL1 locus than has been reported for other Caucasian populations previously.

Long-term results of anterior cruciate ligament reconstruction: a comparison with non-operative treatment with a follow-up of 17–20 years

PurposeThe aim of our study was to review the clinical and radiological outcome of patients who had undergone anterior cruciate ligament (ACL) reconstruction in comparison to a group of non-operatively treated patients.MethodsIn a retrospective study we compared ACL reconstruction using a bone-patellar tendon-bone graft with a non-operatively treated group of patients 17–20 years later. Fifty-four patients that met the inclusion criteria, with arthroscopically proven ACL rupture, were treated between 1989 and 1991. Thirty-three patients underwent ACL reconstruction, forming group one. Eighteen non-reconstructed patients continued with rehabilitation and modification of activities (group two). The International Knee Documentation Committee (IKDC) subjective and objective evaluation forms and the Lysholm and Tegner scale were used to assess the knees at follow-up. Radiographic assessment was performed using the IKDC grading scale.ResultsFollow-up results showed that 83% of reconstructed patients had stable knees and normal or nearly normal IKDC grade. Patients in the non-reconstructed group had unstable knees with 84% having abnormal or severe laxity. The subjective IKDC score was significantly in favour of group one: 83.15 compared to 64.6 in group two. The Lysholm and Tegner score was also significantly better in group one. Conservatively treated patients all had unstable knees and worse scores. The rate of osteoarthritis showed more severe changes in non-reconstructed patients with additional meniscus injury.ConclusionsWe can conclude that 94% of patients who underwent ACL reconstruction had stable knees after 15–20 years and there was a significantly lower percentage of osteoarthritis in comparison to conservatively treated patients.

Bone Morphogenetic Protein–7 (Osteogenic Protein–1) Promotes Tendon Graft Integration in Anterior Cruciate Ligament Reconstruction in Sheep

Background Bone morphogenetic proteins induce new bone both in patients with bone defects and at extraskeletal sites in animals. After anterior cruciate ligament rupture, tendon graft fixation into a bone tunnel is a widely used method for anterior cruciate ligament reconstruction. Hypothesis Bone morphogenetic protein–7 applied to the bone-tendon interface enables better integration of a free tendon graft into the surrounding bone. Study Design Controlled laboratory study. Methods The anterior cruciate ligament was reconstructed using a free tendon graft in the right rear knees of 30 one-year-old male sheep. Recombinant human bone morphogenetic protein–7 (25 μg) was applied randomly to the bone-tendon interface in 15 animals, and a vehicle was applied in 15 control animals. At 3 weeks, 10 animals from each group were sacrificed, and the remaining sheep were sacrificed at 6 weeks after surgery. Subsequently, histologic analysis and mechanical testing were performed. In another group of 20 sheep, the same procedure was used and mechanical testing was performed after 3 weeks. Results More new bone was formed at the bone-tendon interface in the knees treated with bone morphogenetic protein–7 as compared histologically with similar areas in control animals, creating areas of dense trabecular network with significantly greater invasion of the tendon fibrous tissue into the bone marrow space. Mechanical testing showed greater strain resistance to force (368 N) in the knees treated with bone morphogenetic protein–7 than in control specimens (214 N). There was no difference between mechanical testing of samples from 3 and 6 weeks after surgery. Conclusion Bone morphogenetic protein–7 promotes complete tendon graft integration into the newly formed surrounding trabecular bone in the reconstruction of the anterior cruciate ligament. Clinical Relevance Bone morphogenetic protein–7 in tendon graft integration might be successfully used in reconstructive surgery of ligaments.

Role of interleukin-1 inhibitors in osteoarthritis: an evidence-based review.

Osteoarthritis (OA), the most common chronic musculoskeletal disease, represents a leading cause of disability in the elderly population worldwide. At present, there is no aetiological treatment for OA patients. Also, current therapeutic regimens for OA are only partially effective, and that is the main reason for most physicians’ complaints. Therefore, one of the biggest challenges in the future will be to find the most appropriate therapy or therapies for OA. Currently, there are three basic modalities of treatment: nonpharmacological, pharmacological and surgical. Regarding pharmacological treatment, numerous molecular pathways involved in the pathophysiology of OA have been investigated as potential therapeutic targets. In preclinical and clinical trials, many compounds and agents have been tested, and some of them have already shown positive effects on the progression of knee and/or hip OA. One such possible pharmacological treatment of OA is anticytokine therapy. Interleukin-1 (IL-1), as a main inflammatory and catabolic cytokine in the pathophysiology of OA, represents one of the possible treatment targets. For specific inhibition of IL-1 production or activity, various treatment strategies could be used. These include the inhibition or modification of IL-1 action through the application of IL-1 receptor antagonist proteins, soluble IL-1 receptors, monoclonal antibodies against IL-1 or against IL-1 receptor I, blocking the formation of active IL-1β, blocking the IL-1 cellular signalling pathways, or using gene therapy. All the abovementioned treatment strategies for specific inhibition of IL-1 production or activity have been investigated in numerous preclinical and clinical studies. Some of these investigations led to the discovery of new potential drugs for the treatment of OA. However, the results of treatment with these drugs were not entirely satisfactory, and further research is required to achieve the desired goals of therapy.

Associations of the Interleukin-1 Gene Locus Polymorphisms with Risk to Hip and Knee Osteoarthritis : Gender and Subpopulation Differences.

Genetic predisposition to the complex hereditary disease like osteoarthritis (OA) of the large joints (hip and knee) includes the interleukin‐1 gene (IL‐1) cluster on chromosome 2. Using a case–control study with 500 OA patients (240 knee and 260 hip OA patients, all with joint replacement), we analysed frequencies of IL‐1 gene cluster polymorphisms in Croatian Caucasian population. The control samples came from 531 healthy individuals including blood donors. We genotyped two single nucleotide polymorphisms in the IL‐1 gene locus at IL‐1A (−889, C>T, rs1800587) and IL‐1B (+3594, C>T, rs1143634) and compared their frequencies between patients and controls. We predicted haplotypes by combining current data with our previous results on gene polymorphisms (IL‐1B, rs16944 and the IL‐1 receptor antagonist gene [IL‐1RN] variable number tandem repeat [VNTR]) for the same population. Haplotype analyses revealed gender disparities and showed that women carriers of the 1‐2‐1‐1 haplotype [IL‐1A(rs1800587) – IL‐1B(rs1143634) – IL‐1B(rs16944) – IL‐1RN(VNTR)] had sixfold lower risk to develop knee OA. However, carriers of the 1‐1‐1‐2 haplotype of both sexes had over twofold higher predisposition to hip OA. Our results differ from some earlier studies in Caucasian subpopulations, which may be due to the fact that this is the first study to separate genders in assessing the IL‐1‐locus genetic risk of OA. The results suggest that inflammatory mediators like IL‐1 might be implicated in the pathogenesis of primary OA in large joints and that as yet unidentified gender‐specific factors exist in a Croatian Caucasian population.

Emerging Pathways and Promising Agents with Possible Disease Modifying Effect in Osteoarthritis Treatment

Current modalities for osteoarthritis (OA) treatment are partially safe and effective, and only alleviate the disease symptomatology, but do not modify progression and structural changes of the disease. At present, there is no approved safe and effective disease-modifying OA drug (DMOAD) for clinical application. Therefore, there is an urgent need for discovery of DMOAD in order to treat OA. Hopefully, the new DMOADs would also pave the way for better understanding of OA pathophysiology. Given the fact that there is still no adequate remedy that will modify the course of OA, a number of emerging pathways and promising agents with possible DMOAD effect arise targeting cartilage, synovial membrane, and subchondral bone, or using stem cell therapy, and gene therapy. All these methodologies will be described and discussed in this review. Available treatment methodologies for OA are unsatisfactory. In order to properly treat OA in the future, more realistic option will be the use of multiple drugs, instead of single therapy, which is likely to be ineffective in the treatment of such heterogeneous diseases. Which combination of drugs with DMOAD effect will be suitable for the treatment of OA, remains to be determined in future studies.

Susceptibility to large‐joint osteoarthritis (hip and knee) is associated with BAG6 rs3117582 SNP and the VNTR polymorphism in the second exon of the FAM46A gene on chromosome 6

Family with sequence similarity 46, member A (FAM46A) gene VNTR and BCL2‐Associated Athanogene 6 (BAG6) gene rs3117582 polymorphisms were genotyped in a case–control study with 474 large‐joint (hip and knee) osteoarthritis (OA) patients and 568 controls in Croatian population by candidate‐gene approach for association with OA. We found that BAG6 rs3117582 SNP genotypes were associated with protection (major allele homozygote) and susceptibility (major–minor allele heterozygote) to OA. BAG6 rs3117582 major allele (A) was associated with reduced risk to OA while the minor allele (C) was associated with increased risk to OA. We identified 6 alleles harboring 2 to 7 repeats making 20 genotypes for FAM46A. A rare FAM46A VNTR genotype comprising VNTR alleles with four and seven repeats (c/f) was associated with increased OA risk in both genders. The genotype with four and six repeats (c/e) was also associated with increased risk to OA in males. A polymorphic FAM46A allele with six repeats (e) was associated with reduced risk to OA in females. Our results suggest association between the FAM46A gene, BAG6 gene and OA in Croatian population, respectively. This is the first study to show associations between these genetic loci and OA.

Failed Anatomical Shoulder Arthroplasty: Case Example 1

Four-part fractures in elderly patients are often treated by shoulder arthroplasty. Depending on the status of the greater tuberosity, anatomical or reverse shoulder prosthesis can be used. If the anatomical prosthesis is used, the greater tuberosity must be fixed to the implant or to the humeral shaft in order to enable normal function of the rotator cuff. Non-healing of the greater tuberosity will signify failed function of the shoulder.

Management and Consequences of the Rotator Cuff Calcific Tendinopathy

Calcific tendinopathy of the rotator cuff represents a treatment challenge since there is no consensus on its treatment. Unfortunately, up to 38 % of the calcifications do not disappear with time. The persistence of the calcification is detrimental to the tendon biology and resistance. Thus, it is mandatory to follow up the calcification and to treat it in case it would not reabsorb spontaneously. Nonsteroidal anti-inflammatory drugs, rest, exercises, physiotherapy, and shock wave therapy are being used with varying results. Those who have not benefited from the conservative measures are indicated for nonsurgical invasive interventions or surgical treatment. Invasive interventions include steroid/anesthetic injection, barbotage (multiple needle punctures), aspiration, and ultrasound lavage. Surgical (arthroscopic) treatment should be reserved for chronic cases or for cuff ruptures due to the deposit.