Daniel Holderbaum
Case Western Reserve University
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Arthritis & Rheumatism | 1999
Jf Bleasel; A R Poole; Dick Heinegård; Tore Saxne; Daniel Holderbaum; Mirela Ionescu; P Jones; Roland W. Moskowitz
OBJECTIVE The Arg5l9-Cys mutation in type II collagen results in severe, precocious familial osteoarthritis (OA) in 100% of carriers within the first 3 decades of life. The carrier population provided a well-defined patient population for the study of serum markers of familial OA with respect to pathogenesis, diagnosis, and prognosis. METHODS Serum was obtained from 31 mutation-positive individuals and 16 mutation-negative individuals. OA severity was determined by clinical and radiologic assessments. Levels of serum cartilage oligomeric matrix protein (COMP), keratan sulfate (KS) epitope, the 846 epitope of aggrecan, and the C propeptide of type II collagen (CPII) were measured and were correlated with the radiologic findings. RESULTS COMP and KS levels, both of which have been suggested to be indicative of disturbed cartilage turnover, were significantly elevated in mutation-positive individuals and in the individuals with OA regardless of mutation status. There was no statistically significant difference between mutation-positive, mutation-negative, OA-positive, and OA-negative individuals with respect to serum concentrations of epitope 846 or CPII, both of which are putative markers of cartilage repair. CONCLUSION Study of the macromolecular constituents of cartilage released into serum in subjects with familial OA revealed altered metabolism in OA, as demonstrated by elevated COMP and KS levels. Other constituents, the 846 epitope and CPII, were not altered, indicating dissociation of cartilage anabolism and breakdown. Future sequential studies will provide an opportunity to define biochemical changes as familial OA develops and to monitor therapeutic responses.
Human Mutation | 1998
Jane F. Bleasel; Daniel Holderbaum; Valeria Brancolini; Roland W. Moskowitz; Eileen L. Considine; Darwin J. Prockop; Marcella Devoto; Charlene J. Williams
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. Hum Mutat 12:172–176, 1998.
Osteoarthritis and Cartilage | 1995
Charles J. Malemud; Robert S. Papay; Thomas M. Hering; Daniel Holderbaum; Victor M. Goldberg; Tariq M. Haqqi
The proteoglycans synthesized by human osteoarthritic femoral head cartilage and nonarthritic articular cartilage age-matched to the osteoarthritic cartilage specimens was studied in explant cultures and in chondrocytes generated by explant outgrowth from the cartilages. Twenty-four hours after explanation, both nonarthritic articular cartilage and osteoarthritic cartilage synthesized principally one large proteoglycan core protein that migrated on 3-5% acrylamide gels with an apparent molecular mass (M(r)) of approximately 520 kDa after enzymatic digestion with chondroitinase ABC and keratanase. The proteoglycan was found in both the explant itself and in the medium compartment of the culture as well. This proteoglycan contained chondroitin-6-sulfate, keratan sulfate and the hyaluronan binding region as evidenced by immunoblotting with murine anti-proteoglycan monoclonal antibodies indicating that the proteoglycan was aggrecan. To a much lesser extent two additional proteoglycan core proteins were also found in the explant but were not seen in the culture medium compartment. These proteoglycans possessed apparent M(r)s of approximately 480 kDa and approximately 390 kDa on 3-5% acrylamide gels after chondroitinase ABC and keratanase digestion. The medium compartment contained principally the approximately 520 kDa proteoglycan core protein. In osteoarthritic cartilage explants, the pattern of newly synthesized proteoglycans recovered from the tissue as assessed on 3-16% polyacrylamide gradient gels remained relatively the same from day 1 after explantation up to 36 days of culture. By contrast, the proteoglycans recovered from the culture medium contained chondroitin sulfate and keratan sulfate after 1, 7, and 21 days in culture but by 36 days appeared to contain only chondroitin sulfate. Chondrocytes generated from osteoarthritic cartilage and age-matched nonarthritic articular cartilage synthesized different patterns of large (greater than 200 kDa) proteoglycan. Whereas chondrocytes derived from osteoarthritic cartilage continued to synthesize principally the approximately 520 kDa proteoglycan core protein, the chondrocytes derived from nonarthritic cartilage synthesized in addition to this proteoglycan, abundant amounts of the other two proteoglycan core proteins as well.
Arthritis & Rheumatism | 1999
Daniel Holderbaum; Tariq M. Haqqi; Roland W. Moskowitz
The Journal of Rheumatology | 1995
Bleasel Jf; Bisagni-Faure A; Daniel Holderbaum; Vacher-Lavenu Mc; T. M. Haqqi; Roland W. Moskowitz; Menkes Cj
The Journal of Rheumatology | 1996
Bleasel Jf; Daniel Holderbaum; V. Mallock; T. M. Haqqi; H. J. Williams; Roland W. Moskowitz
Molecular Genetics and Metabolism | 2001
Richard J. Mier; Daniel Holderbaum; Rebecca Ferguson; Roland W. Moskowitz
Biochemical and Biophysical Research Communications | 1993
Daniel Holderbaum; Charles J. Malemud; Roland W. Moskowitz; Tariq M. Haqqi
Journal of Immunology | 1994
Robert A. Ortman; Daniel Holderbaum; Xue Mei Qu; Subhashis Banerjee; Tariq M. Haqqi
The Journal of Rheumatology Supplement | 1995
Bleasel Jf; Daniel Holderbaum; Haqqi Tm; Roland W. Moskowitz