Articular Calcified Cartilage Research Articles

Calcium pyrophosphate dihydrate and basic calcium phosphate crystal-induced arthropathies: update on pathogenesis, clinical features, and therapy.

Calcium-containing crystals are the most common class for the osteoarthritic joint. They are responsible for acute periarthritis and destructive arthropathies, and for tissue deposits mimicking tumor-like masses. These crystals encompassed mainly calcium pyrophosphate dihydrate and basic calcium phosphate crystals, with the latter being related to hydroxyapatite, carbonate-substituted apatite, and octacalcium phosphate. Calcification deposit mechanisms will be reviewed with respect to extracellular inorganic pyrophosphate dysregulation mainly caused by modulation of specific membrane channel disorders. Genetic defects have been extensively studied and identified mutation of specific genes such as ANKH and COL. Pathogenesis of crystal-induced inflammation is related to synovial tissue and direct cartilage activation. Besides classical knee or wrist pseudogout attacks or Milwaukee shoulder arthropathies, clinicians should be aware of other specific common presentations, such as erosive calcifications, spinal cord compression by intraspinal masses, ligamentum flavum calcification, or atypical calcified tophus. Promising clinical results for preventing calcium crystal deposits and cartilage degradation are lacking. Practical imaging tools are needed to monitor reduction of calcification of fibrocartilage and articular cartilage as markers of drug efficacy.

Nanomechanical properties and mineral concentration in articular calcified cartilage and subchondral bone.

We studied articular calcified cartilage (ACC) and the immediately subchondral bone (SCB) in normal and osteoarthritic human femoral heads. Thick slices of human normal reference post mortem (PM) and osteoarthritic (OA) femoral heads (age 55-89 years) were embedded in PMMA, micromilled, carbon coated and studied using quantitative backscattered electron (qBSE) imaging to determine variations in degree of mineralization. With exact microanatomical location, nanoindentation was performed on the same block faces in representative superior (more highly loaded) and medial regions of the joint surface. Using a partial unloading method, elastic modulus as a function of indenter penetration depth was determined using a spherical tipped diamond indenter. A pointed indenter was used to determine the tissue hardness in selected locations. The relationship between mineralization and indentation modulus was more distinct in ACC than in SCB, the latter having a higher matrix concentration with variable collagen orientation. In OA, the bulk of the measurements were coincident with those in the PM samples, although there was a greater range in the levels of mineralization and modulus in ACC. In OA, extremely hypermineralized ACC was found in ACC proper, especially in superior regions, and translocated into SCB and hyaline cartilage. The very highly mineralized cartilage fragments may function as a hard grinding abrasive, accelerating wear rates whether attached to or fragmented from the eburnated surfaces of OA ACC. Highly mineralized regions would also alter loading patterns and thereby contribute to further destruction of the joint tissues.

Linked deficiencies in extracellular PP(i) and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression.

Osteopontin and PP(i) both suppress hydroxyapatite deposition. Extracellular PP(i) deficiency causes spontaneous hypercalcification, yet unchallenged osteopontin knockout mice have only subtle mineralization abnormalities. We report that extracellular PP(i) deficiency promotes osteopontin deficiency and correction of osteopontin deficiency prevents hypercalcification, suggesting synergistic inhibition of hydroxyapatite deposition. Nucleotide pyrophosphatase phosphodiesterase (NPP) isozymes including PC-1 (NPP1) function partly to generate PP(i), a physiologic calcification inhibitor. PP(i) transport is modulated by the membrane channel protein ANK. Spontaneous articular cartilage calcification, increased vertebral cortical bone formation, and peripheral joint and intervertebral ossific ankylosis are associated with both PC-1 deficiency and expression of truncated ANK in ank/ank mice. To assess how PC-1, ANK, and PP(i) regulate both calcification and cell differentiation, we studied cultured PC-1 -/- and ank/ank mouse calvarial osteoblasts. PC-1 -/- osteoblasts demonstrated approximately 50% depressed NPP activity and markedly lowered extracellular PP(i) associated with hypercalcification. These abnormalities were rescued by transfection of PC-1 but not of the NPP isozyme B10/NPP3. PC-1 -/- and ank/ank cultured osteoblasts demonstrated not only comparable extracellular PP(i) depression and hypercalcification but also marked reduction in expression of osteopontin (OPN), another direct calcification inhibitor. Soluble PC-1 (which corrected extracellular PP(i) and OPN), and OPN itself (> or = 15 pg/ml), corrected hypercalcification by PC-1 -/- and ank/ank osteoblasts. Thus, linked regulatory effects on extracellular PP(i) and OPN expression mediate the ability of PC-1 and ANK to regulate calcification.

Metabolic and Endocrine Arthropathies

<h2>Abstract</h2> Articular cartilage calcification caused by deposition of calcium pyrophosphate dihydrate (CPPD) is more common in women than in men. The prevalence increases with age; the condition is uncommon under 50 years, but is seen in the knee in up to 60% of individuals aged over 85 years. It may be asymptomatic, may occur in association with osteoarthritis (in which the possible pathogenic role of the crystal is uncertain) or may present as acute pseudogout or associated with chronic arthritis.

Articular cartilage calcification and matrix vesicles.

There has been much research in calcium-containing crystal deposition diseases of hereditary and sporadic type. Synovial cell-induced inflammation and secondary cartilage damage are common in these diseases. In most cases of these diseases and in primary osteoarthritis, there are mineral deposits in the cartilage, mineral crystals in the synovial fluid, and aberrations of pyrophosphate metabolism.

Effect of load on articular cartilage matrix and the development of guinea-pig osteoarthritis

Objective To study the biochemical changes in the early development of primary guinea-pig knee osteoarthritis (OA) and its dependence on load.Methods Load distribution was modified with below-knee amputation or femur valgus osteotomy in 9-month-old guinea-pigs. Soft tissue sham operated animals served as controls. The composition of uncalcified and calcified articular cartilage at the medial and lateral tibial condyle was studied by analysing small and large proteoglycans (PG) by gel electrophoresis and sulfation pattern with high-performance liquid chromatography. Collagen concentration was also determined.Results The articular surfaces with a presumed higher load after surgery had a slight, but consistent, higher water content. Decreased load—on the ipsilateral medial condyle after femur osteotomy, and on the ipsilateral medial and lateral condyles following tibia amputation—was associated with an increased concentration of PGs, while this concentration decreased in condyles with increased load. Collagen concentration followed a similar pattern in the osteotomy group. In the amputated animals collagen concentration went down in all condyles, regardless of change of load. The aggregability and proportion of large and small PGs, the concentration of hyaluronan and the sulfation pattern of chondroitin sulfate was not affected by load. No consistent changes in PG, collagen or HA concentration, HA aggregability or sulfation pattern were seen in the calcified cartilage.Conclusions Primary guinea-pig knee OA is a reproducible model similar to human OA. It develops slowly and biochemical changes seem to appear before the morphological lesions become evident. The biochemical events are affected by load redistribution and correlate closely to morphological changes. These changes eventually result in a cartilage devoid in aggrecan, as also has been demonstrated in advanced human OA. All of this makes primary guinea-pig OA a suitable model for studying early OA changes.

Paleohistology of the bones of pterosaurs (Reptilia: Archosauria): anatomy, ontogeny, and biomechanical implications

Thin sections from long bones of specimens representing pterosaurs ranging from the Early Jurassic to the latest Cretaceous provide a profile of bone histology across a range of sizes, skeletal elements, growth stages, and phylogenetic positions. Most pterosaur bone is fibro-lamellar, organized in an unusual way that suggests high growth rates through ontogeny. Fibro-lamellar deposits are finished by a relatively abrupt deceleration or cessation of growth represented by lamellar, poorly vascularized subperiosteal bone in what appear to be adults. Pterosaurs had the thinnest bone walls of any tetrapods; they complemented high rates of periosteal deposition with almost equally high rates of endosteal erosion. Pterosaurs show a great variety of histologic features that include articular calcified cartilage, sub-chondral bone plates, trabecular bone struts and related internal supports, and secondary deposition and remodeling of bone. They remodeled their bones internally by (1) depositing endosteal bone coatings on the inner cortex and over struts of pre-existing internal bone, (2) secondarily filling bone spaces, and (3) Haversian reworking. The construction of these struts reflects both developmental patterns of bone construction and biomechanical function. Alternating plywood-like layers of bone, heretofore undescribed in tetrapods, provided strength, as did the obliquely oriented system of reticular blood vessels in the bones. The distribution and ontogenetic features of pterosaur bone tissues, when combined with other evidence, suggest generally high growth rates, high metabolic levels, altricial birth, and extended parental care.

Palaeohistology of the bones of pterosaurs (Reptilia: Archosauria): anatomy, ontogeny, and biomechanical implications

Thin sections from long bones of specimens representing pterosaurs ranging from the Early Jurassic to the latest Cretaceous provide a profile of bone histology across a range of sizes, skeletal elements, growth stages, and phylogenetic positions. Most pterosaur bone is fibro-lamellar, organized in an unusual way that suggests high growth rates through ontogeny. Fibro-lamellar deposits are finished by a relatively abrupt deceleration or cessation of growth represented by lamellar, poorly vascularized subperiosteal bone in what appear to be adults. Pterosaurs had the thinnest bone walls of any tetrapods; they complemented high rates of periosteal deposition with almost equally high rates of endosteal erosion. Pterosaurs show a great variety of histologic features that include articular calcified cartilage, sub-chondral bone plates, trabecular bone struts and related internal supports, and secondary deposition and remodeling of bone. They remodeled their bones internally by (1) depositing endosteal bone coatings on the inner cortex and over struts of pre-existing internal bone, (2) secondarily filling bone spaces, and (3) Haversian reworking. The construction of these struts reflects both developmental patterns of bone construction and biomechanical function. Alternating plywood-like layers of bone, heretofore undescribed in tetrapods, provided strength, as did the obliquely oriented system of reticular blood vessels in the bones. The distribution and ontogenetic features of pterosaur bone tissues, when combined with other evidence, suggest generally high growth rates, high metabolic levels, altricial birth, and extended parental care.

New developments in the pathogenesis of articular cartilage calcification.

Articular cartilage, unlike growth plate cartilage, is specialized to not undergo matrix calcification. However, articular cartilage mineralization, in the form of CPPD (chondrocalcinosis) and hydroxyapatite crystals, frequently accompanies and complicates osteoarthritis and aging. Recent work has demonstrated that certain features of growth cartilage development and mineralization are shared in degenerative cartilage. These include chondrocyte proliferation, hypertrophy and increased apoptosis. Moreover, parathyroid hormone related protein (PTHrP), one of the central mediators of endochondral development, is abundant in osteoarthritic cartilage. Cartilage PPi elaboration and cytosolic transglutaminase activity are markedly increased with aging. Only recently have the molecular identities been defined for the chondrocyte inorganic pyrophosphate (PPi)-generating isozymes of the phosphodiesterase nucleotide pyrophosphatase (PDNP) family (including PC-1 and B10), and for transglutaminase in articular cartilage. This review focuses on the evolving understanding of the potential roles, in articular cartilage calcification, of PTHrP, PDNP family enzymes, PPi metabolism, and transglutaminase activity.

Chondrocalcinosis of the hyaline cartilage of the knee: MRI manifestations.

To determine the ability of MRI to detect the presence of crystals of calcium pyrophosphate in the articular cartilage of the knee. The MR studies of 12 knees (11 cases) were reviewed retrospectively and correlated with radiographs (12 cases) and the findings at arthroscopy (2 cases) and surgery (1 case). A total of 72 articular surfaces were evaluated. Radiographic, surgical or arthroscopic demonstration of chondrocalcinosis was used as the gold standard. Additionally, two fragments of the knee of a patient who underwent total knee replacement and demonstrated extensive chondrocalcinosis were studied with radiography and MRI using spin-echo T1-, T2- and proton-density-weighted images as well as two- and three-dimensional fat saturation (2D and 3D Fat Sat) gradient recalled echo (GRE) and STIR sequences. MRI revealed multiple hypointense foci within the articular cartilage in 34 articular surfaces, better shown on 2D and 3D GRE sequences. Radiographs showed 12 articular surfaces with chondrocalcinosis. In three cases with arthroscopic or surgical correlation, MRI demonstrated more diffuse involvement of the articular cartilage than did the radiographs. The 3D Fat Sat GRE sequences were the best for demonstrating articular calcification in vitro. In no case was meniscal calcification identified with MRI. Hyperintense halos around some of the calcifications were seen on the MR images. MRI can depict articular cartilage calcification as hypointense foci using GRE techniques. Differential diagnosis includes loose bodies, post-surgical changes, marginal osteophytes and hemosiderin deposition.

Chondrocyte-derived apoptotic bodies and calcification of articular cartilage.

Chondrocytes exposed to nitric oxide (NO) or antibody to Fas undergo cell death by apoptosis. This study examines structural and functional properties of chondrocyte-derived apoptotic bodies. In NO treated cartilage, the dense pericellular matrix that normally surrounds the cells is degraded and apoptotic bodies accumulate within and in the vicinity of the chondrocyte lacunae. Functional analysis shows that apoptotic bodies isolated from NO-treated chondrocytes or cartilage produce pyrophosphate. The levels of pyrophosphate produced by apoptotic bodies are increased by pretreatment of the chondrocytes with transforming growth factor beta and decreased by interleukin 1. Apoptotic bodies contain alkaline phosphatase and NTP pyrophosphohydrolase activities and can precipitate calcium. These results suggest that chondrocyte-derived apoptotic bodies express functional properties that may contribute to the pathologic cartilage calcification observed in aging and osteoarthritis.

Ultrastructural immunolocalization of bone sialoprotein in guinea-pig osteoarthritis

In diarthrodial joints, bone and cartilage are structurally and functionally inseparable as shown in osteoarthritis (OA), where subchondral bone changes are integral in the disease process. By ultrastructural immunohistochemistry using polyclonal antibodies against guinea-pig bone sialoprotein (BSP), we investigated the distribution of this matrix protein at the osteocartilaginous interface in Hartley guinea-pig knees at different stages of primary osteoarthritis. Between 6 and 12 months they developed moderate osteoarthritic changes predominantly in the medial condyle, progressing to severe OA at 30 months. In all age groups BSP labeling was concentrated to the osteocartilaginous interface at a 1 micron narrow zone at the interface. In the medial osteoarthritic condyle, BSP was increased as compared with the lateral nonosteoarthritic condyle, but only at 30 months, when cartilage fibrillation correlated to BSP. Our observations suggest that altered BSP abundance may be a potential bone marker for late stage OA, while early events in bone cannot be monitored. BSP is expressed early in osteogenesis and may have a role in biological mineralization and growth. Since a sharp zone of intense BSP labeling remains at a remarkably constant level throughout life in guinea-pigs, BSP may have an important structural and/or regulating role at the interface. The protein may act as an anchor of calcified articular cartilage to subchondral bone or by regulating mineralization at the osteocartilaginous interface.

Microcracks in articular calcified cartilage of human femoral heads

Microcracks in articular calcified cartilage of human femoral heads

Localization of type X collagen in canine growth plate and adult canine articular cartilage

Type X collagen was extracted from ends of canine growth plates by pepsin digestion after 4 M guanidine hydrochloride extraction, purified by stepwise salt precipitation (2.0 M NaCl in 0.5 M acetic acid), and chromatographed on a Bio-Gel A1.5 M column in 1.0 M CaCl2. Without reduction on sodium dodecyl sulfate (SDS) polyacrylamide gels, the preparation yielded a single, high-molecular-weight (mol wt) band; after reduction, a single band of relative mol wt 5.0 x 10(4) was found. Polyclonal sera were raised against the purified collagen and used in the immunolocalization of canine type X collagen. As expected, indirect immunoperoxidase (IP) or indirect immunofluorescent staining with the polyclonal sera demonstrated that most of the immunoreactivity was localized in the zone of provisional calcification of the growth plate and in cartilage remnants in the metaphyseal region of the physis. A progressive decrease in staining toward the diaphysis of the fetal canine long bone was apparent as the trabecular structures were remodeled to bone. Unexpectedly, type X collagen was also detected in the zone of calcified, mature articular cartilage. It was concentrated in the pericellular matrix of the chondrocytes, appeared at or just above the tidemark, and was expressed immediately before mineralization. Identification of type X collagen in both the canine growth plate and the zone of calcified articular cartilage suggests that cells in the deep layer of cartilage and in the zone of calcified cartilage in the adult animal retain some characteristics of a growth plate and may be involved in regulation of mineralization at this critical interface. The expression of growth plate-like properties would allow the deep chondrocytes of mature articular cartilage to play a role in remodeling of the joint with age and in the pathogenesis of osteoarthritis.

Ultrastructure of the mineralizing metacarpophalangeal joint of progressive ankylosis (ank/ank) mice.

The metacarpophalangeal joint of the progressive ankylosis mouse was examined at 4, 6 and 8 weeks of age by using electron microscopy and electron probe microanalysis. These studies describe the progression of the disorder, and they reveal three overlapping phases: pannus proliferation, chondrophyte formation and mineralization, and articular cartilage mineralization. The chondrophyte mineralized in a manner fairly similar to endochondrial bone, whereas articular cartilage mineralized by advancement of a calcification front across the cartilage. Synovial crystal phagocytosis was also observed. The progressive ankylosis mouse should be an important model for studying both crystal deposition and abnormal articular cartilage calcification.

Experimental hydroxyapatite synovial and articular cartilage calcification: light and electron microscopic studies.

Intraarticular calciphylaxis with cartilage and synovial calcification was produced in rabbits by oral administration of a single dose of dehydrotachysterol followed by an intraarticular injection of ferrous chloride. Synovial membrane apatite deposits were seen in the interstitium, on collagen fibers, and within cell vacuoles. In contrast, long-term administration of dehydrotachysterol alone induced only articular cartilage calcification. Such calcification was limited to the mid and deep zone of cartilage. Most calcium deposits were apatite-like crystals. Acute crystal-associated inflammation was not demonstrated in these specimens with crystals sequestered in synovial or cartilage tissue. Further studies on these models will examine the relation of apatite to joint disease.

The maturation and aging of the vertebrae of marmosets.

This study deals with the growth, maturation, and age changes to the cartilaginous end-plates of vertebrae from marmosets (Callithrix jacchus) varying in age from birth to 10 years. The cartilaginous end-plate is divided into an inner growth layer and an outer articular zone that abuts against the intervertebral disc. The growth cartilage gradually narrows and disappears by 1 year of age, when the animal reaches physical maturity. The articular cartilage undergoes changes in collagen and ground substance that leads to its calcification. There was a progressive resorption of the calcified articular cartilage beginning at 3 years of age and continuing throughout the aging period. In the vertebrae of 8- and 10-year-old animals, only a thin layer of calcified cartilage separates the disc from the underlying bone.

Calcification of aging articular cartilage in man.

Calcification of the articular cartilage was studied ultrastructually using normal femoral heads obtained from necropsies of persons ranging in age from 11 months to 80 years. Mineral crystals which appeared during the initial stages of deposition were morphologically divided into two types. Type A crystals were slender, twisted and curved, measuring from 100 nm to 360 nm in length. Type B crystals were short, needle-like and slightly curved, measuring from 30 nm to 160 nm in length. Type A crystals were found mainly in the developing epiphysis during childhood. Type B crystals were generally found in the calcified zone of adult articular cartilage. Both types of crystals initially appeared in close proximity to extracellular membrane-invested electron dense particle called "matrix vesicles", and gradually increased in number to form calcified cartilage matrix. The morphological differences between type A and B crystals might be caused by biochemical alterations of the cartilage matrices and/or biomechanical changes in the joints of children and adults.

Chondrocalcinosis and chondrocalsynovitis (pseudogout syndrome): Analysis of twenty-four cases

Analysis of twenty-four cases of articular chondrocalcinosis reveals that in five chondrocalcinosis appeared in association with other rheumatic diseases but of the remaining nineteen cases there was otherwise unexplained acute or subacute arthritis in twelve (63 per cent) at some time during the illness, and chronic symptoms of joint involvement, characterized mainly by low grade arthralgias, in ten (53 per cent). Hyperuricemia with or without gouty arthritis was found in six of nineteen cases in which uric acid studies were carried out, suggesting a possible relationship between hyperuricemia and chondrocalcinosis. Roentgenologic evidence of calcification was most commonly seen in the knees, both as calcification of menisci and articular hyaline cartilage. Crystals characteristic of calcium pyrophosphate dihydrate were found in the majority of cases but the findings of crystals with birefringent properties consistent with dicalcium phosphate dihydrate suggests that other crystalline deposits may give similar clinical findings. The etiology of the abnormal calcification is unknown. In certain forms the disease may be the result of a primary defect in calcification with secondary degenerative changes, in others calcification appears to be secondary and follows primary degenerative change. Treatment of the acute attack is symptomatic. Joint fluid aspiration usually gives significant relief, especially when combined with intra-articular steroids when feasible. In addition, various antiinflammatory agents, including phenylbutazone, oral corticosteroids and, at times, salicylates and colchicine, appear to be of value. Associated disease states such as hyperparathyroidism and hemochromatosis should be sought and ruled out. The number of cases of articular chondrocalcinosis and chondrocalsynovitis which has rapidly accumulated since the syndrome was emphasized recently testifies to its relative frequency as a cause of articular symptoms and future studies should establish further its importance as a rheumatologic entity.

Primary Articular-Cartilage Calcification with Arthritis (Pseudogout Syndrome)

1. A recently described disease consisting of articular-cartilage calcification with polyarthritis is discussed. 2. The literature is reviewed and four new cases are presented. 3. The roentgenographic picture is characteristic, consisting of calcification in the intermediate zone of articular cartilage. 4. The diagnosis is established by identifying crystals of calcium pyrophosphate in aspirated joint fluid by x-ray diffraction. 5. A theory of pathogenesis of the arthritis is presented.