Mutations in osteoprotegerin account for the CCAL1 locus in calcium pyrophosphate deposition disease.

OBJECTIVE: Mutations on chromosomes 5p (CCAL2) and 8q (CCAL1) have been linked to familial forms of calcium pyrophosphate deposition disease (CPDD). Mutations in the ANKH gene account for CCAL2, but the identity of CCAL1 has been elusive. Recently, a single Dutch kindred with a mutation in the Tumor Necrosis Factor Receptor Super Family member 11B (TNFRSF11B) gene coding for osteoprotegerin (OPG) was described as a gain-of-function mutation. Affected family members had premature generalized osteoarthritis (PGOA) and CPDD. As the TNFRSF11B gene is on 8q, we sought additional evidence that TNFRSF11B was CCAL1, and investigated potential disease mechanisms. DESIGN: DNA from two novel PGOA/CPDD families was screened for sequence variants in the TNFRSF11B gene. Mutations were verified by genotype analysis of affected and unaffected family members. We also investigated effects of normal and mutant OPG on regulators of CPP crystal formation in porcine cartilage. RESULTS: The identical TNFRSF11B mutation described in the Dutch family was present in two novel PGOA/CPDD families. ANKH was normal in affected patient fibroblasts. Exogenous OPG did not alter ANKH mRNA or protein levels, affect translocation of ANKH to the membrane, nor increase [pyrophosphate (PPi)] or other key regulators of CPDD. CONCLUSION: We have firmly established the identity of CCAL1 as TNFRSF11B (OPG). Our findings suggest that this mutation produces disease in an ANKH-independent manner via novel mechanisms not primarily targeting cartilage. This work rationalizes further investigation of OPG pathway components as potential druggable targets for CPDD.

The adverse effects of diabetes on osteoarthritis: update on clinical evidence and molecular mechanisms.

Projected increases in the prevalence of both diabetes mellitus (DM) and osteoarthritis (OA) ensure their common co-existence. In an era of increasing attention to personalized medicine, understanding the influence of common comorbidities such as DM should result in improved care of patients with OA. In this narrative review, we summarize the literature addressing the interactions between DM and OA spanning the years from 1962 to 2014. We separated studies depending on whether they investigated clinical populations, animal models, or cells and tissues. The clinical literature addressing the influence of DM on OA and its therapeutic outcomes suggests that DM may augment the development and severity of OA and that DM increases risks associated with joint replacement surgery. The few high quality studies using animal models also support an adverse effect of DM on OA. We review strengths and weaknesses of the common rodent models of DM. The heterogeneous literature derived from studies of articular cells and tissues also supports the existence of biochemical and biomechanical changes in articular tissues in DM, and begins to characterize molecular mechanisms activated in diabetic-like environs which may contribute to OA. Increasing evidence from the clinic and the laboratory supports an adverse effect of DM on the development, severity, and therapeutic outcomes for OA. To understand the mechanisms through which DM contributes to OA, further studies are clearly necessary. Future studies of DM-influenced mechanisms may shed light on general mechanisms of OA pathogenesis and result in more specific and effective therapies for all OA patients.

Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis.

OBJECTIVE: Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury. DESIGN: Rat knee joint models were used to mimic cartilage defects after acute injury. Immunohistochemistry was performed to detect proteins related to fibrosis. Human fetal chondrocytes and bone marrow stromal cells (BMSCs) were used to study the influence of the lipid lysophosphatidic acid (LPA) on COL I synthesis. Quantitative PCR, ELISA and immunohistochemistry were performed to evaluate the production of COL I. Chemical inhibitors were used to block LPA signaling both in vitro and in vivo. RESULTS: After full-thickness cartilage injury in rat knee joints, stromal cells migrating to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX); intact articular cartilage in rat and humans expressed negligible levels of ATX despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in COL I production by chondrocytes and BMSCs were mediated by the MAP kinase and PI3 Kinase signaling pathways. Inhibition of the ATX/LPA axis significantly reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage defects in rats in favor of the collagen II-enriched normal state. CONCLUSION: Taken together, these results identify an attractive target for intervention in reducing the progression of post-traumatic fibrosis and osteoarthritis.

Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway.

OBJECTIVE: Bisphosphonates are commonly used anti-osteoporotic drugs which have controversial effects on joint diseases including osteoarthritis. Certain bisphosphonates have been shown to have anabolic effects on cartilage which could have important ramifications for their proposed effects in vivo; however, the underlying mechanisms are poorly understood. Thus, the purpose of this study was to characterize the effects of clodronate on primary articular chondrocyte metabolism and to determine the underlying signaling pathways responsible. DESIGN: The effects of clodronate and pamidronate on extracellular matrix (ECM) biosynthesis, accumulation and MMP-13 activity were observed in high density, 3D cultures of bovine articular chondrocytes for up to 4 weeks were evaluated. Mechanisms were delineated by measuring intracellular Ca(2+) signaling and the effects of pharmacologic inhibition of the purinergic receptor pathway. RESULTS: Clodronate (100 µM) induced an anabolic effect (increased biosynthesis by 13-14%) which resulted in an 89-90% increase in ECM accumulation after 4 weeks of culture and without an associated effect on matrix turn-over. Stimulation by clodronate resulted in a 3.3-fold increase in Ca(2+) signaling and pharmacological inhibitor experiments suggested that the anabolic effects exerted by clodronate are transduced through the purinergic receptor pathway. CONCLUSIONS: These findings support the previous notion that certain bisphosphonates may be useful as adjunctive therapies to potentially ameliorate progression of cartilage degeneration and improve arthritis management.

Purine receptors modulate chondrocyte extracellular inorganic pyrophosphate production.

OBJECTIVE: Extracellular inorganic pyrophosphate (ePPi) plays a key role in the regulation of normal and pathologic mineralization. The purpose of this work was to evaluate the role of P1 and P2 purine receptors in modulating ePPi production by articular chondrocytes. METHODS: Porcine cartilage explants and chondrocyte monolayers were cultured in the presence of P1 agonists, or a P2 agonist or antagonist and inhibitors of P2 signaling. Ambient media ePPi concentrations were measured after 48-96h. RESULTS: The P1 agonists NECA and CGS 21680 significantly decreased ePPi concentrations surrounding chondrocytes and cartilage explants. The P2 agonist, ADP, increased ePPi levels, and the P2 antagonist, suramin, decreased ePPi concentrations. Thapsigargin and 1,2 bis-(2-aminophenoxy)ethane-N,N,N'N'-tetra acetic acid (BAPTA), which dampen Ca(2+)-related P2 signaling, suppressed the response to ADP. CONCLUSIONS: Purine receptors are important regulators of ePPi production by chondrocytes. P1 receptor stimulation diminishes and P2 receptor stimulation enhances ePPi production. Alterations in receptor signaling or aberrations of extracellular purine nucleotide metabolism resulting in abnormal quantities or proportions of P1 and P2 receptor ligands could foster changes in ePPi production that in turn affect mineralization. We propose a homeostatic role for extracellular purine nucleotides and purine receptors in stabilizing ePPi concentrations.

Characterization of articular calcium-containing crystals by synchrotron FTIR.

OBJECTIVE: Sixty percent of synovial fluids from patients with severe osteoarthritis (OA) contain calcium pyrophosphate dihydrate (CPPD) or basic calcium phosphate (BCP) crystals. These bioactive crystals can be particularly difficult to accurately identify in complex biologic systems, such as in vitro models of crystal formation. We sought to determine if synchrotron Fourier Transform Infrared spectroscopy (sFTIR) could be used to identify and characterize calcium-containing crystals in mineralization models. METHODS: CPPD and BCP crystals from porcine models of crystal formation were examined with an FTIR Microscope attached to a synchrotron light source. As a comparison, crystals from human synovial fluids were also examined. The sFTIR spectra generated were compared with known spectra of multiple forms of BCP and CPPD crystals, as well as spectra generated by synthetic CPPD and BCP crystals and cartilage proteoglycans, alone and in mixtures. RESULTS: sFTIR readily identified CPPD and BCP crystals in porcine models as well as in fresh synovial fluids. Brushite was also present in human and porcine samples, and whitlockite was seen in some porcine samples. Mixtures of minerals were commonly found in a single crystal aggregate in both human and porcine samples. In spectra from many CPPD crystals, the peak at the 1134 cm(-1) found on the standard spectrum for CPPD was diminished. Addition of spectra from cartilage proteoglycans to those of synthetic CPPD crystals dampened the peak at this frequency region, much as this peak was diminished in biologically derived CPPD crystals. CONCLUSION: sFTIR analysis allows for accurate identification of CPPD and BCP crystals generated in vitro and will be a useful research tool to study articular crystals.

Thyroxine stimulates transglutaminase activity in articular chondrocytes.

OBJECTIVES: Thyroid hormones induce features of the hypertrophic phenotype in mature articular chondrocytes as well as in growth plate chondrocytes. Hypertrophic chondrocytes are responsible for extracellular matrix mineralization, with formation of bone mineral in growth plate cartilage and pathologic calcium crystals in aging articular cartilage. Elevated activity levels of the two transglutaminase (Tgase) enzymes (type II Tgase and Factor XIIIA (FXIIIA)) have recently been described as additional features of hypertrophic growth plate chondrocytes. Because Tgases may participate in pathologic mineralization in aging cartilage, we explored the effects of thyroid hormones on Tgase activity in articular chondrocytes. METHODS: Adult porcine articular chondrocytes were incubated with or without 250-750nM L-thyroxine (T4) or 10-100 nM 3,3',5-tri-iodothyronine (T3). Tgase activity was measured with a standard radiometric assay. The effects of thyroid hormones on protein and mRNA levels of type II Tgase and FXIIIA were determined. As Tgase activity can be stimulated by proteases, endoproteinase levels were also measured. The mechanisms of these effects were explored. RESULTS: T4 (750 nM) or T3 (100 nM) stimulated Tgase activity by twofold in articular chondrocytes at 4h and increased the percentage of Tgase activity in the extracellular matrix. Chondrocytes rapidly converted T4 to T3, but the time course suggests similar mechanisms for T4 and T3. T4-induced Tgase activity was suppressed with cycloheximide and protein kinase C inhibitors. The effects of T4 on type II Tgase and FXIIIA levels were modest, but T4 strongly induced endoproteinase activity in chondrocytes. CONCLUSIONS: We report in this study that thyroid hormones increase Tgase activity in articular chondrocytes via a non-genomic mechanism, which may involve increased endoproteinase secretion.

The transglutaminase, Factor XIIIA, is present in articular chondrocytes.

OBJECTIVES: The transglutaminase (TGase) family includes seven different enzymes that catalyse a protein cross-linking reaction resulting in structural and functional alterations in substrate proteins. TGase activity is easily measureable in mature articular cartilage where it may contribute to CPPD deposition disease through its actions on growth factors, crystal components or extracellular matrix proteins. In contrast, low levels of TGase activity are found in chondrocytes from young animals. We previously demonstrated type II TGase protein in articular chondrocytes. Earlier work also suggested the presence of another form of TGase in chondrocytes. We sought to determine if articular chondrocytes contain the TGase, Factor XIIIA (FXIIIA). METHODS: Western blots with FXIIIA antibody were used to detect FXIIIA in young and old porcine articular chondrocytes and articular cartilage vesicles (ACVs). The presence of FXIIIA mRNA was confirmed by RT-PCR. RESULTS: Old chondrocyte conditioned medium, cytosol, and membrane fractions contained FXIIIA protein on Western blots, while less FXIIIA was detectable in cell fractions or media from young chondrocytes. ACVs also contained FXIIIA. FXIIIA mRNA was demonstrated by PCR in old and young chondrocytes. CONCLUSIONS: FXIIIA is present in articular chondrocytes. FXIIIA levels correlate with TGase activity in chondrocytes. The presence of two forms of TGase in articular chondrocytes suggest an important function for this enzyme family in articular cartilage.

Transforming growth factor beta-1 stimulates articular chondrocyte elaboration of matrix vesicles capable of greater calcium pyrophosphate precipitation.

Objective To determine the role of transforming growth factor beta1 (TGFbeta) in early calcium pyrophosphate formation by measuring its effects on articular chondrocyte matrix vesicle (MV) formation, specific activity of the inorganic pyrophosphate(PPi)-generating enzyme nucleoside triphosphate pyrophospho-hydrolase (NTPPPH) and biomineralization capacity. Methods MV elaborated from mature porcine chondrocyte monolayers+/-TGFbeta were compared for protein content, NTPPPH activity, and ATP-dependent biomineralization. Precipitation of calcium pyrophosphate mineral phases by MV was determined by a radiometric assay and by Fourier transform infrared spectroscopy (FTIR). Results MV from monolayers exposed to TGFbeta were enriched in NTPPPH activity compared to MV from control monolayers (P< 0.01) and precipitated more calcium/mg MV protein than controls (P

Identification of crystals in synovial fluids and joint tissues.

The identification of crystals in synovial fluids and joint tissues is the most rapid and accurate method of diagnosing the common forms of crystal-associated arthritis. Although there are numerous methods available for identifying and characterizing crystals in biologic specimens including x-ray crystallography and Fourier transform infrared spectroscopy, in practice, polarizing light microscopy is used almost exclusively for articular crystals. Unfortunately, problems with reliability and reproducibility undercut the usefulness of this simple procedure. This article highlights recent developments in the field and discusses the importance of identifying synovial fluid crystals, proper handling of specimens, and the appropriate use of available technologies for crystal identification.

Pathogenesis of calcium pyrophosphate crystal deposition disease.

Calcium pyrophosphate dihydrate deposition (CPPDD) disease is an increasingly common form of arthritis affecting the elderly. It is characterized by the formation of CPPD crystals in articular cartilage and usually results in severe cartilage destruction with loss of joint function. This article discusses our understanding of how and why these crystals form, highlighting recent developments in the field.

Transglutaminase participates in the incorporation of latent TGFbeta into the extracellular matrix of aging articular chondrocytes.

TGFbeta1 is a multifunctional peptide growth factor that promotes processes associated with age-related degenerative diseases in articular cartilage. Large quantities of TGFbeta1 are stored in cartilage extracellular matrix (ECM) in a latent form (LTGFbeta1), and yet little is known about the factors that participate in the incorporation of LTGFbeta1 into the highly specialized cartilage ECM. We previously demonstrated high levels of the protein cross-linking enzyme transglutaminase (TGase) in aging articular chondrocytes and showed that this enzyme participated in LTGFbeta1 activation. This work explores the hypothesis that extracellular TGase participates in LTGFbeta1 incorporation into ECM in aging chondrocytes. We studied the effects of TGase inhibitors on TGFbeta1 levels in ECM of old and young porcine articular chondrocytes. TGase inhibitors decreased the quantity of LTGFbeta1 in the ECM in old but not in young chondrocytes to 60-70% of control values (p<.05). Fibronectin, an extracellular TGase competitive substrate, also decreased LTGFbeta1 levels in ECM (p<.01). Levels of activated TGFbeta1 also decreased in the presence of TGase inhibitors, as did levels of latent TGFbeta binding protein 1 in the cell layer. Extracellular TGase activity was present in old but not young chondrocyte cultures. These findings support a role for extracellular TGase in the incorporation of LTGFbeta1 in the ECM of aging chondrocytes.

Participation of transglutaminase in the activation of latent transforming growth factor beta1 in aging articular cartilage.

OBJECTIVE: Transglutaminase (TGase) catalyzes the calcium-dependent crosslinking of polypeptide chains, resulting in posttranslational protein modifications that affect both intracellular and extracellular processes. We previously demonstrated a dramatic elevation of TGase activity levels in aging articular chondrocytes and postulated a role for TGase in the pathologic processes common in aging joints. In several cell systems, TGase participates in the activation of latent transforming growth factor beta (LTGFbeta). Since TGFbeta is a key factor in age-related cartilage diseases, the purpose of the present study was to determine whether TGase from aging articular chondrocytes participates in LTGFbeta activation. METHODS: We measured the ability of old and young porcine articular chondrocytes to activate 10 ng/ml of LTGFbeta1 in the presence and absence of TGase inhibitors. The activity of plasmin, another key participant in LTGFbeta activation, was also measured. RESULTS: Old chondrocytes activated 11+/-1.8% (mean +/- SD) of exogenous LTGFbeta1 at 6 hours, while young chondrocytes activated 4.2+/-0.5% of exogenous LTGFbeta1. The addition of 3 different TGase inhibitors suppressed active TGFbeta1 in the cell layer to levels that were 35-69% of control values in old chondrocytes and had no effect on young chondrocytes. The ability to suppress TGFbeta activation correlated with the ability of each of the TGase inhibitors to inhibit TGase activity. The activity of plasmin, which enzymatically activates LTGFbeta1, did not differ between young and old chondrocytes and was unaffected by TGase inhibition. CONCLUSION: We report here a novel pathologic function for TGase in aging articular cartilage. This work supports a role for elevated TGase activity in age-related arthritis based in part on its participation in the activation of the critical growth factor TGFbeta in articular cartilage.

Connective tissue disease and other related rheumatic conditions among patients with finger and hand and temporomandibular joint prostheses in Denmark.

OBJECTIVE: To determine if finger and hand joint prostheses or temporomandibular joint (TMJ) implants may be involved in the initiation of specific connective tissue diseases (CTD), a nationwide cohort in Denmark was followed prospectively to evaluate rates of CTD after receiving these implants. METHODS: Danish patients with finger and hand joint implants (n = 562) or TMJ implants (n = 351) were identified and followed for subsequent hospitalizations. Observed numbers of hospitalizations due to CTD were compared with expected numbers based on national CTD hospitalization rates. To avoid confounding by indication, patients with a hospital discharge diagnosis of a CTD prior to prosthetic surgery were excluded from the cohort. RESULTS: After 4142 person-years of followup in the finger and hand joint cohort, 9 hospitalizations due to CTD were found [standard hospitalization rate (SHR) = 1.5; 95% CI 0.7-2.9]. The TMJ cohort had 1500 person-years of followup and 2 hospitalizations due to CTD (SHR = 1.3; 95% CI 0.2-4.5). CONCLUSION: This is the first cohort study to examine the relations between these implants and CTD. Although the number of events was small, this systematic national study revealed no significant or large increase in risk of CTD after finger and hand joint implants or TMJ implants.

Formation of calcium pyrophosphate crystals: biologic implications.

The formation of calcium pyrophosphate dihydrate (CPPD) crystals in articular cartilage marks the earliest known phase of CPPD deposition disease. Although the exact mechanisms through which these crystals form remains unknown, work over the last year has added useful details to our current paradigms of crystal nucleation and growth. Key advances include (1) progress in understanding pyrophosphate elaboration and its modifiers, (2) further characterization of the enzymes responsible for pyrophosphate elaboration, and (3) the discovery of an association between two seemingly unrelated metabolic risk factors for CPPD deposition disease.

Hepatic angiosarcoma occurring after cyclophosphamide therapy: case report and review of the literature.

A 54-year-old man with polyarteritis nodosa developed acute onset of right upper quadrant abdominal pain associated with a large liver mass. Transvenous liver biopsy revealed hepatic angiosarcoma, a rare liver tumor classically associated with environmental toxins. He had been treated with oral cyclophosphamide for 13 years. A review of the literature revealed two other cases of hepatic angiosarcoma in patients after long-term cyclophosphamide treatment. We propose that cyclophosphamide be added to the list of exposures potentially associated with hepatic angiosarcoma.

Thyroid hormones induce features of the hypertrophic phenotype and stimulate correlates of CPPD crystal formation in articular chondrocytes.

OBJECTIVE: Articular cartilage affected by calcium pyrophosphate dihydrate (CPPD) crystal deposition contains abnormal chondrocytes with morphologic similarities to the terminally differentiated hypertrophic chondrocytes that mineralize in growth plate cartilage. These chondrocytes also elaborate high levels of extracellular inorganic pyrophosphate (PPi), an essential component of the CPPD crystal. Several factors that stimulate articular chondrocyte PPi elaboration also induce terminal differentiation in growth plate chondrocytes. We hypothesized that factors such as thyroid hormones (T3 and T4) that are potent stimulants of growth plate chondrocyte hypertrophy might also stimulate articular chondrocyte hypertrophic differentiation. We also hypothesized that like transforming growth factor-beta (TGF-beta), ascorbate, and retinoic acid, thyroid hormones would increase chondrocyte PPi elaboration. METHODS: We determined the effects of T3, T4, and TGF-beta on markers of the hypertrophic phenotype such as alkaline phosphatase (ALPase) activity and type X collagen production; and the effects of T3 and T4 on processes implicated in CPPD crystal formation including PPi elaboration and nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity in adult porcine articular chondrocytes in culture. RESULTS: ALPase activity increased 3-fold with T3 and T4 and 1.3-fold with TGF-beta. Type X collagen levels also increased with thyroid hormone treatment. [125I]T3 binding studies proved the existence of saturable T3 receptors on chondrocytes. Media [PPi] and cellular NTPPPH activity significantly increased in cultures treated with 1-10 nM T3 or 100-500 nM T4. CONCLUSION: Increased PPi elaboration is an additional and previously unrecognized feature of hypertrophic differentiation in articular chondrocytes. These terminally differentiated chondrocytes may play a pathogenic role in CPPD crystal deposition disease.

Calcium crystal-associated arthritides.

Articular calcium-containing crystals cause calcium pyrophosphate dihydrate (CPPD) deposition disease, basic calcium phosphate (BCP)-associated syndromes, and calcium oxalate arthritis. During the past year, important contributions have been made to our understanding of CPPD- and BCP-related syndromes. Clinical studies of CPPD deposition disease underscore the importance of extra-articular and spinal CPPD deposits, and question the association between hypothyroidism and chondrocalcinosis. Laboratory reports add key information to our current paradigms of CPPD crystal formation and CPPD-induced inflammation. Several interesting new therapeutic interventions may arise from this work. A case collection of BCP-related syndromes emphasizes the need for considering this diagnosis in young healthy patients with acute arthritis or periarthritis.

Transglutaminase activity in aging articular chondrocytes and articular cartilage vesicles.

OBJECTIVE: Transglutaminases (TGases) (E.C. 2.3.2.13) catalyze a posttranslational modification of proteins and are associated with biomineralization in growth plate cartilage. Type II TGase participates in the activation of latent transforming growth factor beta (TGFbeta), a crucial factor for both normal cartilage mineralization and the pathologic mineralization that results in calcium pyrophosphate dihydrate (CPPD) crystal formation in aging articular cartilage. To explore a possible association between TGase levels and CPPD crystal formation in mature articular cartilage, TGase activity in articular chondrocytes from old and young pigs and in the articular cartilage vesicle (ACV) fraction of porcine articular cartilage was examined. In addition, the effects of TGase inhibitors on the production of inorganic pyrophosphate (PPi), a process necessary for CPPD crystallogenesis, were determined. METHODS: TGase activity was measured with a radiometric assay in cultured articular chondrocytes from the knee joints of old (3-5 years old) and young (2-6 weeks old) pigs and in the ACVs. PPi levels were measured in chondrocyte-conditioned media in the presence of TGase inhibitors or control compounds. RESULTS: Levels of TGase activity in the cytosolic fraction of old chondrocytes were 7-fold higher than those in identically cultured young chondrocytes. The mean +/- SD activity level in the membrane fraction of lysed chondrocytes was 6.0 +/- 0.6 units/mg protein in old articular chondrocytes and was undetectable in young chondrocytes. In ACVs, the mean +/- SD TGase activity level was 1.23 +/- 0.1 units/mg protein. Type II TGase protein was present in chondrocyte cytosol and in ACVs. TGase activity was increased by TGFbeta to 120% of control values (P < 0.01), and decreased by insulin-like growth factor 1 to 80% of control values (P < 0.01). TGase inhibitors blocked media accumulation of PPi, an essential precursor of CPPD crystal formation, and a sensitive marker of TGFbeta effect. CONCLUSION: These data suggest a potential link between TGase activity and processes of pathologic biomineralization that result in CPPD crystal formation in aging articular cartilage.

Hemochromatosis-like arthropathy in diabetes mellitus without hemochromatosis.

We describe 3 patients with non-insulin-dependent diabetes mellitus who presented with hand pain and swollen joints. All 3 had radiographic changes in the affected joints typical of those associated with hemochromatosis. None of these patients had hemochromatosis. This is the first description of hemochromatosis-like arthropathy in diabetes mellitus without hemochromatosis.