A biography of the chondrocyte.

Significant gaps persist in our understanding of chondrocyte biology. We do not know when, how, or even whether these cells are replenished throughout the normal, human life span. We are taught that as much as 90% of the cartilage is "metabolically inert" interterritorial matrix, but we do not know how this substance is regularly replaced (as it is known to be) by the distant chondrocytes, We recognise that the "tidemark" is the most conspicuous histological feature within cartilage, but we do not understand why that layer stains with haematoxylin or what that may imply for the biology of the tissue. These, and other issues may be clarified if the lifetime of each chondrocyte begins as a mesenchymal stem cell at the articular margin, plays out over years on an arcing trajectory along collagenous guidelines, and ends as an extracellular deposit of intracellular remains at the interface between uncalcified and calcified cartilage. This hypothesis is presented here, and some of its potential implications are considered.

Antirheumatic drug concentrations in human synovial fluid and synovial tissue. Observations on extravascular pharmacokinetics.

Antirheumatic drug concentrations have been measured in human synovial fluid and synovial tissue, and provide insights on: (1) extravascular pharmacokinetics; (2) articular pathophysiology; and (3) the factors which modify drug levels in inflamed tissues. Concentrations of free drug in synovial fluid and plasma are the same in all conditions except rheumatoid and infectious arthritis, where the most severely afflicted joints may contain lower synovial fluid drug concentrations. This finding may be relevant to the chronicity and intractability of chronic arthritis. After single-dose therapy and a characteristic 'equilibration time', higher concentrations are found in synovial fluid than in plasma - a phenomenon which results from relative drug sequestration across the trans-synovial diffusion barrier away from the organs of elimination. Studies of oral, parenteral, topical and intra-articular antirheumatic drug therapy are reviewed, and recommendations are made for the conduct of future studies.

Articular pharmacokinetics of protein-bound antirheumatic agents.

By what mechanism do nonsteroidal anti-inflammatory drugs (NSAIDs) move from plasma into synovial fluid and back, and how does binding to plasma albumin in vitro relate to articular transport in vivo? To evaluate these issues, concurrent plasma and synovial fluid data of 8 different NSAIDs from 10 single-dose trials were analysed by a simple compartmental model incorporating intra-articular volume, synovial plasma flow rates and protein transport. All pharmacological and physiological data were taken from published studies of chronic knee effusions in patients with rheumatoid arthritis. The analysis shows that these protein-bound NSAIDs readily leave the vasculature and enter synovial fluid during each transit of synovial microvessels. The mean rate of transport, 0.23 min-1, is consistent with passive diffusion at rates far in excess of those attributable to movement of albumin-bound drug or of the small, free-drug fraction found by equilibrium dialysis. These findings are explained by association and dissociation of NSAIDs and albumin that occur far more rapidly than vascular transit. Ongoing dissociation makes bound drug available for transvascular exchange and thereby diminishes the pharmacokinetic significance of binding data obtained in vitro.

Physiology of normal and abnormal synovium.

Because the synovial lining is a major target organ of rheumatic diseases, it seems logical to seek understanding of those conditions through study of the normal and abnormal physiology of this specialized organ system. This brief review covers some basic principles and recent progress in this area with emphasis on our evolving knowledge of microvascular function.

Synovial perfusion in the human knee: a methodologic analysis.

Synovial perfusion was quantified in milliliters per minute per knee by two quite different clearance methods based on (1) counting tritiated water in serial aspirates of intraarticular saline, and (2) external counting of joints injected with free radioiodide. In each case, the serial counting data determine a rate constant that is multiplied by a distribution volume to provide the clearance in flow terms of milliliters per minute. This report updates and summarizes these data and compares the two methods to each other and to alternative assessments of synovial blood flow. Available methods such as laser Doppler flowmetry (with data output measured in volts) and solute clearance constant determinations (in min-1) are useful for selected purposes but cannot be used to quantify the articular flux (in milligrams per minute) of any solute. Radiolabeled microspheres provide data (in milliliters per minute per g of tissue) but are unsuitable for human use. The two clearance methods provide comparable results, but the free iodide technique seems most suitable for physiologic investigations. The latter potentially includes critical evaluations of synovial blood flow in relation to issues such as palpable warmth, visible erythema, articular ischemia, the permeability of synovial vessels, the genesis of effusions, the delivery and removal of therapeutic agents, and the concentration of every synovial fluid solute from micronutrients through cytokines, plasma proteins, and molecular markers of cartilagenous injury.

Subchondral plate thickness reflects tensile stress in the primate acetabulum.

To evaluate possible relationships between body size and articular architecture, femoral head radius and subchondral plate thickness were assessed in skeletal hip joints from normal primates. The relative "contact pressure" on bearing surfaces was estimated from the measured radius and the normal body mass in species ranging from Cebuella pygmaea (0.1 kg) to Gorilla gorilla (170 kg). Subchondral plate thickness was evaluated by computed tomography in species ranging from Cercopithecus neglectus (4.0 kg) to Gorilla gorilla. Neither the "contact pressure" nor the thickness of the femoral subchondral plate varied substantially among species. In contrast, the acetabular subchondral plate thickened significantly (p = 0.01) as body size increased. This finding is interpreted as an osseous response to tensile acetabular stress, which can be expected to increase directly with the radius of curvature.

Effects of exercise on blood flow to canine articular tissues.

We measured articular blood flow by standard microsphere techniques in normal adult dogs at rest and during treadmill exercise. All animals but one underwent beta-adrenergic blockade as part of another experimental protocol. Expressed in microliter/min/g +/- SEM, baseline flow values to articular tissues were: knee synovium 26 +/- 4, femoral condyle 130 +/- 21, tibial plateau 182 +/- 29, articular fat pad 9 +/- 2, knee ligaments 17 +/- 3, menisci 34 +/- 6, wrist synovium 19 +/- 4, distal radius 65 +/- 13, and lunate bone 59 +/- 13. Blood flow increased with exercise in all soft tissues of both the knee (stifle joint) and the wrist (radiocarpal joint). Geometric mean exercise/rest flow ratios ranged from a low of 1.44 (p less than 0.05) in the menisci of the knee to a high of 7.25 (p less than 0.001) in the synovium of the wrist. In contrast, blood flow did not rise in juxtaarticular bones and fell significantly in femoral condyles (mean flow ration 0.71, p less than 0.005). These findings indicate that articular soft tissues derive increased perfusion from the redistribution of blood flow that accompanies short-term exercise. In contrast, flow to juxtaarticular bone does not increase under these conditions.

Hydraulic resistance: a measure of vascular outflow obstruction in osteonecrosis.

This study introduces hydraulic resistance (HR) as a new method to measure intraosseous vascular outflow resistance in the human proximal femur. HR is the standard measure of resistance to fluid flow in porous matrices and is derived from serial pressure/flow determinations. Eighteen hips were studied in 11 patients taken to surgery for core decompression therapy of presumable atraumatic osteonecrosis of the femoral head. HR was much higher in osteonecrotic (174 +/- 29 mm Hg min/ml, SE) than in normal human cadaveric femora (14 +/- 6) and was also higher in subcapital (253 +/- 39) than intertrochanteric sites (78 +/- 17). HR correlated highly with baseline intraosseous pressure (r = 0.74, p less than 0.001). HR testing is a simple, practical method which quantifies outflow obstruction of the intraosseous circulation. We believe this test will be helpful in the diagnosis of atraumatic osteonecrosis and in the understanding of its underlying pathophysiology.

The effect of compressive loading on intraosseous pressure in the femoral head in vitro.

We measured intraosseous pressures in twenty human hips from cadavera during progressive serial applications of load using a materials-testing machine. Pressure rose in strict proportion to load at each of four different testing sites. In the femoral head, the mean response to loads applied over 0.1 second was 55 +/- 66 millimeters of mercury per 980 newtons. This value was 3.6 times higher than the mean response in a region cephalad to the acetabulum and 2.6 and 2.8 times higher than the mean response in the femoral neck and intertrochanteric regions. In further studies within the femoral head, pressures were accentuated and reduced by factors of 1.7 and 0.4, respectively, at faster (0.03 second) and slower (1.0 second) loading times.

Compliance and viscoelasticity of canine shoulders loaded in vitro.

Humeral and scapular components of normal canine shoulders were used to load each other in a special testing jig permitting measurement of subchondral plate deflection on each side of the joint. In eleven shoulders, at three loading rates, the humeral compliance (mu deflection kg load-1) was always greater than that of the glenoid fossa (geometric mean ratio = 6.0). On sustained compression, there was prominent stress relaxation most suggestive of intraosseous hydraulic flow.

Hydraulic resistance in bones of the canine shoulder.

The hydraulic properties of trabecular bone were explored in both sides of normal canine shoulders by following the hydrostatic pressure response to transchondral injections of saline. In a series of isovolumetric injections at sites 9 mm beneath either joint surface, the pressure consistently rose higher and lasted longer in the humerus than it did in the scapula. Hydraulic resistance, the linear function of pressure per unit flow, averaged 8.8 times higher within the humerus than in the scapula in a second series of experiments. Hydraulic resistance fell by average factors of 9.6 in the humerus and 4.3 in the scapula when the surrounding bone was cut away to leave the injection site centered within a 1 cm 'cube' of trabecular bone. Direct determinations of hydraulic resistance provide a useful tool for the study of normal and abnormal physiology in trabecular bone.

Urate metabolism in a mongrel dog.

(1) We have performed short-term turnover studies in a trained mongrel dog, and found remarkably linear turnover curves for both urate and its principle metabolic product, allantoin. (2) Infusions of Pyrazinamide, Probenecid, and Sodium Salicylate had no apparent effect on urate metabolism. (3) The "uricolytic index" for endogenous urate is consistenely lower than that of infused, isotopic urate. This finding suggests renal synthesis and direct excretion of unlabelled urate. (4) The renal clearance of labelled urate is higher than that of endogenous urate despite apparent renal synthesis. This finding suggests that urate may exist in more than one molecular form.

Management of gout and hyperuricemia.

The medical management of gout follows a logical course in eventually controlling the underlying hyperuricemia. Approached properly, it is one of the most gratifying rheumatic diseases for a physician to treat.

Concentration-effect relationships of NSAID.

For the most part, plasma concentrations of nonsteroidal antiinflammatory drugs (NSAID) have not correlated well with assessments of therapeutic response. This disappointing record may largely reflect weaknesses in experimental design. It may also be, however, that concentrations in plasma bear only a distant relationship to those in the inflamed tissues where NSAID presumably act. Elimination kinetics, protein binding, fat solubility, tissue blood flow, and uptake by cells may be determinants of concentration and response in target tissues. These factors are considered as they relate to NSAID concentrations in synovial effusions.