Joint Disease Biochem-Cell BSc 2024 PDF

Biochemical and Cellular Mechanisms in Joint Disease (Arthritis) Andy Pitsillides Professor of Skeletal Dynamics  Necessary background Joint as an organ Cartilage - structural integrity Collagen - Proteoglycans Transient/growth cartilage vs. Permane...

Biochemical and Cellular Mechanisms in Joint Disease (Arthritis) Andy Pitsillides Professor of Skeletal Dynamics  Necessary background Joint as an organ Cartilage - structural integrity Collagen - Proteoglycans Transient/growth cartilage vs. Permanent/articular cartilage homeostasis, breakdown and repair?  Learning Objectives Students should be able to: (a) Describe the major biochemical and cellular abnormalities in arthritic joints (b) Describe pathological processes in joint disease and understand how surrogate markers of joint tissue turnover can be used to monitor joint disease Develop an appreciation of: a) Complexity of joint disease aetiology/ pathogenesis b) Molecular alterations c) How ageing affects joint function d) Potential for therapy in animals and man  Arthritis / Joint diseases Degenerative Inflammatory DJD/Osteoarthritis Infective arthritis Osteochondrosis Non-infective - Autoimmune (RA) - Traumatic - (Crystal-induced) Enzymes from synovial cells and exudate in synovial fluid degrade cartilage: (a) In infection – appropriate, but cartilage caught as “bystander” (b) In autoimmune and crystal-induced disease - inappropriate  What is OA? “Progressive and permanent deterioration of articular cartilage” American College of Rheumatology definition - Osteoarthritis is a "heterogeneous group of conditions that leads to joint symptoms and signs which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins."  Need to consider the Articular Joint as an Organ Cartilage relies on correct functioning of all joint tissues Meniscus Canine Patella Ligaments Bones Muscle Human Mouse Numbers Lacks preceding synovitis Disability, stiffer after rest Fibrillated & soft cartilage surface Joint space narrowing Osteophyte formation Subchondral bone sclerosis Swelling Pain HUMAN OA CLASSIFICATION Hand joints: Primary Causes unidentified and https://www.oarsijournal.com/ typified by insidious article/S1063-4584(22)00805- development 6/fulltext Secondary When etiologic factors can be demonstrated Some joints affected - others spared  UK: 8 million adults (14% population; 0.5% RA) UK: 1.5 million new patients annually Prevalence after 75 yrs: > 80% after 65 yrs: 60% in men; 70% in women under 30 yrs < 1% Leading cause of invalidism at +50 years Global: >300 million Turbo greying Ageing UK Percent of population aged >65 years Proportion of people who have sought treatment for OA  Why Study OA in Animals? 53% of Thoroughbred racehorses lame at some period (£) Musculoskeletal injuries major cause of wastage About 12% of MSK injuries relate to phalangeal joints - Common in Greyhounds and large dogs - Most common in Orthopaedic clinic - Clinical features often 30Kg) all species … bears deer small animals < large (George et al. 1990) Meeson et al., Nature reviews in Rheumatology, 2019  Species similarities? Shorter timeframes? Genetic selection? Meeson et al., 2019. Shoulder OA Nat Rev Rheumatol.15:273-87. - Great Danes Hip avascular OA - Miniature Poodles Experimental: Cranial cruciate ligament transection Pond-Nuki model (1973) Tibia (light) cranially displaced & internally rotated (femur, dark) Normal CCL Knee cruciate ligament failure - Labradors Reduced area and greater femorotibial contact pressure. Dog Human Pozzi et al., 2013. PLOS ONE 8: e81383. Hip dysplasia - Golden Retrievers Equine MCP Joint Risk factors Hypochondriac’s dream Valgus 1.7 cm longer Left Right  Determinants/ Risk Factors (human) Environmental Obesity Overweight = OA incidence in knee and hips Weight loss can reduce knee OA risk in women by 50% (Felson et al. 2004) & >10% weight loss improves long-term pain, physical/mental life quality (Messier SP 2018) Reduced body fat ‘provides symptomatic relief’ – Leptin? Occupation Repetitive tasks that overload joints Specific physical trauma e.g. pneumatic hammers Sports – professional footballers; high intensive activities. Trauma Fractures, torn meniscus, ligaments – joint instability - footballers; skiers; Genetics Sex Bias: a little more prevalent in women Epidemiological studies: Genome scans; twin studies; no loci definitively linked: Alpha estrogen receptor? Vitamin D receptor? IGF-1; TGFbeta1? BUT distinct genetic links (GDF5 polymorphisms) predisposing some (hip) joints Ethnicity: knee OA more common in African-Americans than Caucasians (USA) Aigner and Dudhia, Current Opinion in Rheumatology 2003  Normal vs. OA Cartilage Articular surface fibrilliated Cell division stimulated Matrix components lost Subchondral bone advances 1-5mm < erosion to 1mm of subchondral bone How is this achieved? What are the early and late stages of OA?  Osteophytes bony projection at joint margins in OA Normal: Thin layer of Chondrogenesis: periosteu Cell proliferation, m Hypertrophy of cells at the Ossification: centre (endochondral) Attempt to redistribute Presence of bone and altered loads? marrow From cavities van der at the Kraan and van centreOA&Cart; 15: den Berg (2007), 237  Osteoarthritis The initial biochemical change that occurs in OA cartilage appears to be a loss in the tissue content of proteoglycans, which occurs while the collagen content remains normal. Despite the decrease in the tissue content of proteoglycans, in the early stages of OA, proteoglycan synthesis …… is increased. Brandt K (1985) Normal cartilage OA cartilage? Homeostatic imbalance Imbalance between biosynthetic and catabolic activity Coupled with poor capacity for repair No vasculature / supply of regenerative cells restricted So what drives this process towards OA? - Cellular phenotype shift - Cell Death  Time out Is osteoarthritis a ‘primarily’ inflammation-driven disease? No List 5-6 symptoms that characterise OA -Pain -Inflammation -Swelling -Cartilage mineralisation What are the main OA determinants/ risk factors? -Trauma -Age -Gender / sex -Genetics  What should we be comparing ? Why compare Normal vs. OA Cartilage? Biochemical alterations - in disease (site, location, zone, stage?) - with age Joint diseases most frequent in older animals Must distinguish between joint pathology and normal ageing – vital !! Desire: Effective treatment and repair strategies for diseased cartilage  Age-related changes that occur in proteoglycan Catabolic fragmentation of aggrecan and link protein Wells et al Biochem J 2003; Dudhia et al Biochem J 1996 % G3 domain on aggrecan 100 Hyaluronan binding region 50 G3 domain 20 40 60 80 Age (years) Chief culprits: Matrix-degrading enzymes Proteolytic activity due to MMP-1, MMP-3, MMP-13, and ADAMts4 and ADAMts5 (aggrecanases) MMP13 upregulated in OA  Normal Cartilage Ageing Thickness Normal cartilage OA Degradation 4yrs 55yrs 79yrs 65yrs products of proteoglycan Hyaluronan Proteolytic cleavage – ADAMts-4/5 Aggrecan Bayliss et al Osteoarthritis Cartilage. 2001 9(6):553-60 1. Ratio of new LP: Aggrecan falls to 95%, 15 yrs Routine & cheap - >cost effective than NSAIDs Better materials being developed Therapeutics of Joint Disease: Future How would you like to treat OA? What therapies would be desirable? What should we target?  Stem Cells? A A B B Autologous chondrocyte implantation >10,000 ACI done since 1995 – benefit? Bigger defects? Lets wait ! 5-10yrs