Significance of Serum Tartrate-Resistant Acid Phosphatase in Rheumatoid Arthritis.

Abstract Human serum contains two related isoforms of tartrate-resistant acid phosphatase namely TRACP 5a and TRACP 5b. Serum TRACP 5a protein is increased in about 1/3 of RA sera. This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in rheumatoid arthritis (RA). 118 patients were recruited including 50 with RA (25 with nodules), 26 with osteoarthritis (OA) and 42 with other rheumatic diseases. 26 healthy adults served as controls. Serum TRACP-5a activity, TRACP-5a protein and TRACP-5b activity were determined by in-house immunoassays. C-reactive protein (CRP) was determined by in-house immunoassay using commercial antibodies and CRP. Other commercial markers included bone-specific alkaline phosphatase (bALP), C-telopeptides of type-I collagen (ICTP), cartilage glycoprotein-39 (YKL-40), and IgM rheumatoid factors (IgM-RF). Mean TRACP-5a protein was significantly elevated only in RA compared to healthy control and other disease groups. TRACP 5a protein correlated significantly only with IgM-RF in RA. Among RA patients, mean TRACP 5a protein and IgM RF were significantly higher in nodule formers. In contrast, TRACP-5b activity was slightly elevated in RA and correlated with bALP. ICTP and YKL-40, but not with IgM-RF or CRP. Mean TRACP-5b activity was no different in RA patients with or without nodules. TRACP isoforms could be useful disease markers in RA: TRACP-5a protein may be a measure of systemic inflammatory macrophage burden and disease severity. TRACP-5b activity is a marker for osteoclast number and perhaps local or systemic bone destruction.

SH3BP2 is an Activator of NFAT Activity and Osteoclastogenesis

Heterozygous activating mutations in exon 9 of SH3BP2 have been found in most patients with cherubism, an unusual genetic syndrome characterized by excessive remodeling of the mandible and maxilla due to spontaneous and excessive osteoclastic bone resorption. Osteoclasts differentiate after binding of sRANKL to RANK induces a number of downstream signaling effects, including activation of the calcineurin/NFAT (nuclear factor of activated T cells) pathway. Here, we have investigated the functional significance of SH3BP2 protein on osteoclastogenesis in the presence of sRANKL. Our results indicate that SH3BP2 both increases nuclear NFATc1 in sRANKL treated RAW 264.7 preosteoclast cells and enhances expression of tartrate resistant acid phosphatase (TRAP), a specific marker of osteoclast differentiation. Moreover, overexpression of SH3BP2 in RAW 264.7 cells potentiates sRANKL-stimulated phosphorylation of PLCγ1 and 2, thus providing a mechanistic pathway for the rapid translocation of NFATc1 into the nucleus and increased osteoclastogenesis in cherubism.

Steven A. Lietmana, b, Lihong Yina, b and Michael A. Levinec

aDepartment of Orthopaedic Surgery, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA

bDepartment of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA

cThe Division of Endocrinology, The Children’s Hospital of Philadelphia, 34th & Civic Center Boulevard, Philadelphia, PA 19104, USA

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