Elevated marrow inflammatory cells and osteoclasts in subchondral osteosclerosis in human knee osteoarthritis.

Subchondral osteosclerosis, characterized by an increase of hypomineralized bone material, is a pathological hallmark of osteoarthritis. The cellular components in the subchondral marrow compartment that participate in this aberrant bone remodeling process remain to be elucidated. This study assessed the presence of marrow inflammatory cells and their relative abundance between nonsclerotic and sclerotic tissues in knee osteoarthritis. Bone samples from osteoarthritic knee tibial plateaus were stratified for histological analyses using computed tomography osteoabsorptiometry. Immunohistological analysis revealed the presence of CD20 (B-lymphocyte) and CD68 (macrophage), but not CD3 (T-lymphocyte) immunoreactive mononuclear cells in subchondral marrow tissues and their relative abundance was significantly increased in sclerotic compared with nonsclerotic bone samples. Multinucleated osteoclasts that stained positive for CD68 and tartrate-resistant acid phosphatase, predominantly associated with CD34-positive blood vessels and their abundance was strongly increased in sclerotic samples. Bone-specific alkaline phosphatase activity in outgrowth osteoblasts was induced by conditioned medium from nonsclerotic, but not sclerotic, bone pieces. These results suggest that an interaction between bone-resident cells and marrow inflammatory cells might play a role in aberrant bone remodeling leading to subchondral osteosclerosis. Elevated osteoclast activity in sclerotic bone suggests that bone formation and resorption activities are increased, yet uncoupled, in human knee osteoarthritis.

Use of site-specific antibodies to characterize the circulating form of big insulin-like growth factor II in patients with hepatitis C-associated osteosclerosis.

Hepatitis C-associated osteosclerosis (HCAO) is a rare syndrome of adult-onset osteosclerosis. An understanding of the factor(s) leading to the stimulation of bone formation in these patients may provide novel anabolic approaches for the treatment of osteoporosis. We have demonstrated that HCAO patients have a specific increase in circulating big IGF-II (IGF-IIE) and IGF-binding protein-2 (IGFBP-2) levels, and that IGF-IIE and IGFBP-2 circulate together in a bioavailable, 50-kDa complex. Patients with nonislet cell tumor hypoglycemia (NICTH) also have increased circulating IGF-IIE and IGFBP-2 levels. However, HCAO patients do not exhibit hypoglycemia, nor do NICTH patients exhibit obvious osteosclerosis. Thus, to better understand the reason(s) for the differing clinical manifestations of the IGF-IIE excess in the two syndromes, we characterized IGF-IIE in HCAO and NICTH sera using recently developed antibodies (Ab) recognizing either the full-length IGF-IIE 89-amino acid C-terminal extension peptide (IIE(138-156) Ab) or specific cleavage forms of IGF-IIE (IIE(78-88) Ab and IIE(89-101) Ab). The predominant IGF-IIE form in HCAO serum migrated on SDS-PAGE as a single band at approximately 18 kDa that reacted with the IIE(89-101) Ab. On the other hand, the predominant form in NICTH serum migrated as a doublet of 14 and 16 kDa that reacted with the IIE(78-88) Ab. There results are consistent with differential processing of the IGF-IIE precursor at predicted cleavage sites producing IGF-IIE(1-104) and IGF-IIE(1-88) in HCAO and NICTH, respectively. As these two forms may have differing biological activities and/or targeting properties, our findings may explain at least in part the different manifestations of IGF-IIE overproduction in the two syndromes.

Thrombin, but not bradykinin, stimulates proliferation in isolated human osteoblasts, via a mechanism not dependent on endogenous prostaglandin formation.

Osteolysis or osteosclerosis often occurs in bone tissue adjacent to chronic inflammatory processes. Numerous cytokines and inflammatory mediators have been implicated as osteoclast-activating agents, explaining inflammation-induced bone resorption. In many cases, the cause of the sclerosis seen in these lesions is less thoroughly investigated. We have studied the effects of thrombin and bradykinin, 2 inflammatory mediators, on the rate of proliferation in isolated human osteoblasts (hOBs). Thrombin, at and above 1 U/mL, stimulated the rate of thymidine incorporation into hOBs. The absolute cell number also increased, as measured by an assay based on the detection of cell metabolism. A synthetic peptide ligand for the thrombin receptor enhanced the rate of [3H]thymidine incorporation in hOBs, indicating that thrombin-induced proliferation is mediated via the tetheric thrombin receptor. The thrombin-induced proliferation was not affected by indomethacin, excluding prostanoids as mediators of this effect. Bradykinin did not affect either the rate of thymidine incorporation, or number of cells in long-term cultures of hOBs. In conclusion, the inflammatory mediator, thrombin, stimulates proliferation in isolated human osteoblasts probably via the recently described G-protein-coupled tetheric thrombin receptor. Thrombin may therefore be involved as a mediator of inflammation-induced sclerosis and bone formation.

Type II collagen autoimmunity in otosclerosis and Meniere's Disease.

Antibodies to collagen types I, II, and IV were measured in patients with otosclerosis and patients with Meniere's disease. Levels of antibodies to type II collagen were significantly higher in these patients than in control subjects, while no differences were found among levels of antibodies to collagen type I or type IV. These observations suggest a possible role for type II collagen autoimmunity in the etiology of otosclerosis and Meniere's disease.

[The reactions of human middle ear mucous membrane (author's transl)]. / Reaktionsformen der Mittelohrschleimhaut

Healthy middle ear mucous membrane of newborns differs from the respiratory mucous membrane of the respiratory tract, in that it lacks a mucociliary epithelial pattern and because it has an absence of cells responsible for immunological resistance. Irritations over a short period of time and intensity cause a mucous membrane edema, which leaves behind, when the irritation disappeares, no permanent morphological changes in the structure of the mucous membrane. Severe irritations over a long period of time cause a characteristic change in the epithelium and submucosa: the single layered flat epithelium is replaced by respiratory epithelium; in the submucosa a proliferation of the connective tissue occurs simultaneously with the development of a local immunologically potent, cellular defense system. The actively secretive epithelial cells serve as the means whereby the antibodies are transported to the surface of the mucous membrane. Whereas at the time of mucous membrane edema, serum components (transsudate) are the primary source of the resulting "serotympanum", an increase in viscosity of the mucous allows one to recognize the active secretive work of the metaplastic epithelium. The biochemical composition of the various effusions givens a direct a direct indication of their origin: it is, however, no key to the cause! Only in the case of purulent secretions is it possible to recognize the cause by cellular or bacteriological identification. The same is valid for the norphological changes of the middle ear mucous membrane since the membrane will generally react in a similar manner, even though the types of irritation differ. When the stimulus which brought about the proliferation of the mucous membrane since the membrane will generally react in a similar manner, even though the types of irritation differ. When the stimulus which brought about the proliferation of the mucous membrane and the epithelial metaplasy disappears, the active production of mucous stops. However, a regression to the original condition does not take place: the mucous membrane remains ready to react!

HLA antigens in osteitis condensans ilii and ankylosing spondylitis.

Using a standard microdroplet lymphocyte cytotoxicity test for tissue typing, the distribution of the HLA antigens was determined in 37 female patients; 25 with osteitis condensans ilii (OCI) and 12 with ankylosing spondylitis (AS). Although low back pain was a common feature of OCI, none of these patients exhibited the limitation of spinal involvement, radiological evidence of spondylitis, or progressive clinical course seen in the AS group. Four of the 25 patients with OCI (16 per cent) were B27 positive vs 11 of the 12 patients with AS (92 per cent). These results suggest that OCI is not a variant of AS in women.