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Biomedical subjects

R W Moskowitz

Publications and source records attributed to R W Moskowitz.

At least 37 records · Page 2Linked to original sources
PubMed1998

Five families with arginine 519-cysteine mutation in COL2A1: evidence for three distinct founders.

Arginine519-cysteine mutation in the type II procollagen gene (COL2A1) is known to be associated with mild spondyloepiphyseal dysplasia (SED) and precocious generalized osteoarthritis (OA). Five families have now been identified with this mutation. To determine whether a common founder was responsible for the mutation in these five families, we defined the haplotype of the mutation-bearing chromosome using four restriction fragment length polymorphisms (RFLPs) and the 3'-untranslated region VNTR. Haplotype frequencies were estimated for 69 control samples. Three distinct mutation-bearing haplotypes were identified, with three families sharing a common haplotype. For three distinct haplotypes to have derived from a single founder, three independent recombination events would have had to occur. Thus the arg519 codon appears to represent a possible site of recurrent mutations in COL2A1, an uncommon phenomenon in collagen genes.

Arginine↗
PubMed1998

Increased secretion and activity of matrix metalloproteinase-3 in synovial tissues and chondrocytes from experimental osteoarthritis.

OBJECTIVE: The aim of this study was to define the relative regulation of matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of metalloproteinases-1 (TIMP-1), in chondrocytes and synovium in experimental osteoarthritis (EOA). METHODS: Partial-meniscectomized (PM) rabbits, surgical sham controls (SH), and normal non-surgical controls (N) were killed at times corresponding to early degenerative lesions (4 weeks) and increasingly progressive stages of EOA at 8 and 12 weeks post-PM. MMP-3 activity was measured in conditioned media from chondrocytes and synovium using a peptide cleavage assay with substance P (SP) as the substrate. TIMP-1 was quantitated using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Early degenerative lesions (4 weeks post-PM) were characterized by inflammatory responses in the synovium accompanied by a significant rise of MMP-3 activity in synovial cultures (P < 0.05). At 8 weeks there was no discernible inflammation, and MMP-3 activity in EOA synovial cultures was comparable to that in the controls; this was followed by a second increase in MMP-3 activity in EOA samples at 12 weeks. MMP-3 activity was significantly elevated in EOA chondrocyte cultures at 8 weeks post-PM relative to N controls, corresponding to the most destructive phase of EOA, but not in the early phase (4 weeks) or 'late' degenerative phase (12 weeks). Medium derived from chondrocytes contained little or no TIMP-1. Synovia secreted relatively higher amounts of TIMP-1, and this was elevated at 8 weeks post-PM relative to the SH controls. The majority (approximately 90%) of MMP-3 activity could be inhibited using recombinant TIMP-1 or a hydroxamate MMP inhibitor. Complete inhibition was achieved with EDTA or 1,10 phenanthroline. CONCLUSION: Together, these data indicate that in EOA, MMP-3 is initially upregulated in the synovium which may play a pivotal role in the pathogenesis of cartilage lesions. In contrast, chondrocyte-derived MMP-3 is upregulated in the later phases of EOA, contributing further to progression of cartilage lesions.

Animals↗
PubMed1997

Temporal pattern of cysteine endopeptidase (cathepsin B) expression in cartilage and synovium from rabbit knees with experimental osteoarthritis: gene expression in chondrocytes in response to interleukin-1 and matrix depletion.

OBJECTIVE: To determine the temporal pattern of expression of cathepsin-B in chondrocytes and synovium in experimental osteoarthritis, and to determine possible mechanisms for upregulation and secretion of cathepsin-B from chondrocytes. METHODS: Experimental osteoarthritis was induced with partial medial meniscectomy (PM); sham operated (SH) and normal (N) rabbits were used as controls. Cathepsin-B mRNA expression was assessed with northern blotting with a 32P labelled cDNA probe. Cathepsin-B was measured in conditioned media or cell extracts using a fluorogenic substrate Z-Arg-Arg-AMC. Chondrocyte monolayers were used to determine cathepsin-B expression in response to interleukin-1 beta (IL-1 beta). Cartilage explants were used to test the effect of matrix depletion on cathepsin-B release. RESULTS: Chondrocytes obtained from experimental osteoarthritis knees did not show cathepsin-B mRNA upregulation. However, isolated chondrocytes secreted cathepsin-B into the culture medium. Enzyme release was significantly higher at 8 weeks relative to controls, but not at 12 weeks or 4 weeks. Enzyme released from synovium was significantly higher in PM group compared with SH group at 4 and 8 weeks. IL-1 beta was ineffective in upregulating steady state cathepsin-B mRNA in chondrocytes; however, it upregulated the intracellular enzyme, and this was blocked with cycloheximide. Enzymatic depletion of cartilage matrix after exposure of explants to IL-1 resulted in release of significantly higher amounts of cathepsin-B into the medium by matrix depleted chondrocytes compared with intact explants. CONCLUSIONS: In experimental osteoarthritis, cathepsin-B is upregulated in synovial tissue during the early degenerative phase. Progression of experimental osteoarthritis is accompanied by upregulation of cathepsin-B in cartilage. Cartilage and synovial cathepsin-B levels decline as experimental osteoarthritis advances to more degenerative states. IL-1 upregulates intracellular cathepsin-B by increasing cathepsin-B protein synthesis; it is not an effective stimulus for enzyme secretion. Depletion of cartilage matrix during progression of experimental osteoarthritis may contribute to secretion of cathepsin-B and perpetuation of cartilage destruction.

Animals↗
PubMed1997

Design and conduct of clinical trials in osteoarthritis: preliminary recommendations from a task force of the Osteoarthritis Research Society.

In 1994, a combined committee of the World Health Organization and the International League of Associations for Rheumatology published recommendations for clinical trials for 2 classes of agents for treatment of osteoarthritis (OA) that relieved symptoms but differed in their onset and duration of response, and a third class of agents that may alter the disease process. Recently, the European Group for the Respect of Ethics and Excellence in Science made recommendations for methods to be used in the registration of drugs for OA. Following the 2nd international meeting of the Osteoarthritis Research Society in December 1994, a task force was convened to develop recommendations for the design and conduct of clinical trials in patients with OA. The Task Force had several meetings over the past 16 months, resulting in the preliminary recommendations summarized here.

Clinical Trials as Topic↗
PubMed1996

Growth factors, insulin-like growth factor-1 and growth hormone, in synovial fluid and serum of patients with rheumatic disorders.

OBJECTIVE: Synovial fluid (SF) plays an important role in joint function. We evaluated the growth factors, insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in SF and serum from patients with osteoarthritis (OA), rheumatoid arthritis (RA), gout, pseudogout and diffuse idiopathic skeletal hyperostosis (DISH). DESIGN: Standard radioimmunoassay techniques were used to measure concurrent levels of IGF-1 and GH. SF samples and serum samples were obtained concomitantly from 27 patients with OA, 22 patients with RA, nine men with gout, 14 patients with pseudogout and eight men with DISH. RESULTS: In the case of IGF-1, a comparison of serum and SF levels shows that SF levels of IGF-1 are lower than serum levels in all groups. Men and women gave similar values. In contrast, in the case of GH, all groups, except males with RA, had higher GH values in SF when compared with serum values. Individual patients with other forms of arthritis demonstrated similar relationships. CONCLUSION: The finding that IGF-1 is present in levels about one-half as great in SF as compared with serum suggests that IGF-1 may be produced in lesser amounts or is utilized by the patient in customary joint function. The finding that GH is present in SF at values twice as high, or more, of serum levels in inflammatory arthritides suggests that GH may play a role in the pathophysiology of arthritic disorders.

Arthritis, Rheumatoid↗
PubMed1996

Hereditary osteoarthritis with mild spondyloepiphyseal dysplasia--are there "hot spots" on COL2A1?

OBJECTIVE: To define the genetic basis of a family with an autosomal, dominantly inherited form of spondyloepiphyseal dysplasia (SED) associated with tall stature. METHODS: A 6 generation family with early onset osteoarthritis (OA) associated with mild SED was studied. 14 individuals were examined clinically and radiologically, and DNA analysis was performed on 5. As the clinical pattern of joint involvement and tall stature of affected individuals resembled a family recently reported with an exon 11 mutation in COL2A1, this same mutation was specifically sought. In 2 clinically affected and 3 unaffected family members, exon 11 was amplified by polymerase chain reaction (PCR) followed by restriction enzyme digestion with Asp H1, the enzyme recognition sequence of which is altered by the mutation. The PCR product containing exon 11 was then directly sequenced. RESULTS: OA with widespread involvement of peripheral joints, in addition to spondylodysplasia, was seen in 14 members of the kindred. Affected family members had brachydactyly and were of average to above average height. Asp H1 digestion of the PCR product containing exon 11 in those with clinical disease was consistent with the presence of a mutation. Direct sequencing of this PCR product conclusively showed that a single base substitution was present in those with clinical disease, resulting in an arginine 75-cysteine (Arg75-Cys) mutation. CONCLUSION: We describe a 3rd family with an Arg75-Cys mutation with precocious generalized OA and mild SED. This finding supports the concept of mutational hot spots on COL2A1 related to the hypermutability of the cytosine-guanine doublet.

Adolescent↗
PubMed1996

The appropriate use of NSAIDs in arthritic conditions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important component of therapy for many of the arthritides. They are of value in the treatment of rheumatoid arthritis (RA) and other arthritides with inflammatory characteristics and are frequently used to treat osteoarthritis (OA) when simple analgesics fail to provide relief. There is a great deal of interpatient variability with respect to response to NSAIDs; however, it is currently difficult to predict which patient will respond best to which drug. As a result, NSAID selection is based both on the medical history of the individual patient and the adverse-events profiles of the available agents. In general, patients on NSAIDs should be monitored closely for adverse events, particularly those patients with a history of, or risk factors for, gastrointestinal, renal, or hepatic disease. Use of the cytoprotective agent misoprostol is indicated in patients at high risk for gastrointestinal irritation. Although H2-antagonists in high dosages may be effective in the prophylaxis of gastropathy, there is some concern that use of these agents at usual dose levels may create a potential for adverse events by masking the pain associated with ongoing gastric erosive changes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Guidelines for the medical management of osteoarthritis. Part I. Osteoarthritis of the hip. American College of Rheumatology.

Treatment of patients with OA of the hip should be individualized and tailored to the severity of the disease. In individuals with mildly symptomatic disease, treatment may be limited to patient education, physical and occupational therapy, other nonpharmacologic modalities, and drug therapy with a non-opioid oral analgesic. In patients who are unresponsive to this treatment regimen, the use of an NSAID in addition to nonpharmacologic therapy is appropriate unless it is medically contraindicated. Patients with severe symptomatic OA of the hip require an aggressive approach to decreasing pain, increasing mobility, and improving function; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Guidelines for the medical management of osteoarthritis. Part II. Osteoarthritis of the knee. American College of Rheumatology.

Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.

Administration, Topical↗
PubMed1995

Lysyl oxidase and Maillard reaction-mediated crosslinks in aging and osteoarthritic rabbit cartilage.

Alterations in the integrity of the extracellular matrix play an important role in osteoarthritis. Matrix crosslinks in articular cartilage of the knee were studied in partially meniscectomized rabbits to compare changes due to osteoarthritis with those occurring during aging. Pyridinoline, a lysyl oxidase-initiated crosslink, and pentosidine, a crosslink formed by the Maillard/glycation reaction, were assayed separately on reverse-phase high performance liquid chromatography. A significant increase in the percentage of insoluble collagen was observed in normal 12-month-old rabbits compared with the levels in 3-month-old animals, whereas osteoarthritis was associated with a shift toward more soluble fractions. Total pyridinoline content did not change with age or osteoarthritis. Total pentosidine, however, increased significantly with age but remained constant with osteoarthritis. Analysis of the distribution of crosslinks among solubility fractions indicated a significant shift of pyridinoline from the pepsin-released fraction to the insoluble fraction with osteoarthritis, but no changes were observed with age. Pentosidine distribution shifted toward the pepsin-released fraction in osteoarthritis, with a shift toward the insoluble fraction with age. Because of the low levels of pentosidine present, its precise location, whether collagenous or noncollagenous, remains unclear. However, since pentosidine represents a marker for the overall Maillard reaction, the results of our studies support a role for Maillard reaction products in the aging of extracellular matrix. The shift of pentosidine toward more soluble fractions suggests the presence of matrix degradation and repair in osteoarthritis.

Aging↗
PubMed1995

Type II procollagen gene (COL2A1) mutation in exon 11 associated with spondyloepiphyseal dysplasia, tall stature and precocious osteoarthritis.

OBJECTIVE: To define the clinical, pathological and molecular genetic characteristics of a family with mild spondyloepiphyseal dysplasia (SED) and precocious osteoarthritis. METHODS: The proband was a 46-year-old man with precocious generalized OA, tall stature, mild chondrodysplasia and moderate deafness. His daughter, aged 21, showed similar clinical features. Electron microscopic (EM) analysis of collagen from an affected joint of the proband was performed. DNA was extracted from whole blood on the proband, his affected daughter, unaffected wife and second daughter, to look for a mutation in exons 31 or 11, sites where point mutations have been previously described in mild forms of SED. After finding no mutation in exon 31, exon 11 of COL2A1 was further analyzed. Exon 11 was amplified using polymerase chain reaction (PCR), and screening for the mutation was undertaken using a restriction enzyme digestion, the recognition sequence of which is altered by this point mutation. Sequence analysis was then performed. RESULTS: Electron microscopic (EM) analysis of cartilage from the proband showed thin appearing collagen fibrils organized into parallel lamellar structures. DNA studies revealed a single base change in one allele of exon 11 which produced an arginine to cysteine mutation at position 75 of the triple helix of type II collagen in the proband and his affected daughter. CONCLUSION: This is the 2nd example of an Arginine75-Cysteine mutation associated with SED; in our case, however, contrasting clinical features were present. Recurrent mutations at a few specific sites of COL2A1 suggest the possibility of susceptibility "hot spots" for mutational events.

Adult↗
PubMed1995

Clinical correlations of osteoarthritis associated with single base mutations in the type II procollagen gene.

There are increasing numbers of mutations described in the gene for type II collagen (COL2A1). Recently, COL2A1 mutations were shown to be associated with milder forms of chondrodysplasia, which may present with precocious generalized osteoarthritis (OA). The arginine519-cysteine and the arginine75-cysteine mutations are 2 such sites on COL2A1 where multiple unrelated families have been reported presenting with early onset, generalized OA and chondrodysplasia. The observation of multiple sites where recurrent mutations occur suggests that certain areas of COL2A1 are more prone to mutational events.

Amino Acid Sequence↗
PubMed1994

Biomechanical, radiologic, and histopathologic correlations in the pathogenesis of experimental intervertebral disc disease.

STUDY DESIGN: The desert sand rat, an animal model for spinal degenerative disc disease, was studied for biomechanical, histologic, and radiographic characteristics. Load deformation curves with peak force and force decay, hematoxylin-eosin-stained sections, and lateral radiographs were correlated. OBJECTIVES: The hypothesis that the subchondral bone response preceded or contributed to the degenerative disc disease seen in the desert sand rat was tested. SUMMARY OF BACKGROUND DATA: Intervertebral disc disease spontaneously develops in the desert sand rat during its lifetime. Approximately 50% will have significant disc disease by age 18 months. Previous studies have found metabolic and histologic changes associated with intervertebral disc degeneration in the sand rat. METHODS: Desert sand rats were killed at 3-, 9-, 15-, and 18-month intervals and tested in Rheometrics Solid Analyzer with nondestructive step strain loading to obtain a load deformation curve. Radiographs and histologic sections of each animal were compared. Peak force and force decay were analyzed by level and by age. Analysis of variance and Tukey's methods were applied to data. RESULTS: There were no statistically significant differences in biomechanical data. No histologic changes were noted in the study groups up to 18 months of age. Radiographic differences characterized by subchondral bony sclerosis were noted by 18 months of age. No trends were noted when radiographic grades were compared with force data. CONCLUSIONS: The absence of biomechanical histologic changes in the intervertebral disc per se from 3 through 18 months, with radiographic changes in the subchondral bone, supports the hypothesis that the earliest changes in intervertebral disc disease in this animal model are related to the subchondral bone response.

Animals↗
PubMed1994

Clinical correlations of osteoarthritis associated with a single-base mutation (arginine519 to cysteine) in type II procollagen gene. A newly defined pathogenesis.

OBJECTIVE: To investigate the occurrence and clinical correlation of the arg519-to-cys mutation in the type II procollagen gene in patients with osteoarthritis (OA). METHODS: Sixty-six subjects from 7 families with a strong family history of generalized OA and 13 patients with erosive OA were evaluated clinically and radiologically. Blood samples from 58 subjects in the familial OA group and from all 13 patients with erosive OA were obtained for DNA analysis. Exon 31 of COL2A1, which spans residue 519, was amplified by polymerase chain reaction. RESULTS: The arg519-to-cys mutation was detected in 2 of the 7 families with generalized OA. In these 2 families, the mutation was present in the 2 probands and in 19 other clinically affected family members, as well as in 3 (so-far) clinically unaffected family members (ages 25, 14, and 11 years). It was absent in 18 clinically unaffected members tested. The mutation was associated with a distinctive pattern of early-onset, aggressive, generalized OA with a mild spinal chondrodysplasia. Inheritance was autosomal dominant. No mutation was found in any of the patients with erosive OA. CONCLUSION: The arg519-to-cys mutation defines a new pathogenic factor in generalized OA with characteristic clinical and radiologic features. The demonstration of a mutation in 3 of 8 families with OA studied thus far suggests a significant incidence of genetically related clinical OA.

Adolescent↗
PubMed1994

Prostromelysin and procollagenase genes are differentially up-regulated in chondrocytes from the knees of rabbits with experimental osteoarthritis.

OBJECTIVE: To determine the relative expressions of matrix metalloprotease (MMP) genes pro-MMP1 and pro-MMP3 in the cartilage of rabbits with experimentally induced osteoarthritis (OA), and to assess the role of the chondrocyte in this process. METHODS: OA was induced in rabbits after partial medial meniscectomy. Rabbits were killed at 4 weeks or 8 weeks, and total cellular RNA was prepared from cartilage and probed by Northern blotting with pro-MMP 32P-labeled complementary DNA. Monolayer chondrocytes were used to assess MMP-inducing activity of chondrocyte factor(s). RESULTS: Pro-MMP messenger RNAs (mRNAs) were up-regulated in experimental OA cartilage; pro-MMP3 mRNA expression exceeded that of pro-MMP1. Conditioned medium from OA-derived chondrocytes up-regulated pro-MMP mRNAs in normal chondrocytes. CONCLUSION: Up-regulation of MMP genes in this OA model may contribute to cartilage degradation. Chondrocytes up-regulate MMP genes via an autocrine pathway.

Animals↗