Strontium ranelate causes osteophytes overgrowth in a model of early phase osteoarthritis.

BACKGROUND: Osteoarthritis (OA) involves cartilage changes as well as modifications of subchondral bone and synovial tissues. Strontium ranelate (SR), an anti-osteoporosis compound, which is currently in phase III clinical trial for treatment of OA. Evidences suggest that SR preferably deposited in osteophyte, other than in subchondral bone in early phase of OA. This phenomenon raises concern about its utility for OA treatment as a disease-modifying drug. To evaluate the effect of SR on cartilage, subchondral bone mass and subchondral trabecular bone structure in medial meniscectomized (MNX) guinea pigs. METHOD: Thirty-six 3-month-old male Dunkin Hartley albino guinea pigs received either sham or medial meniscectomy operations. One week after the procedure, meniscectomized animals began 12 weeks of SR (625 mg/kg, daily) treatment by oral gavage for MNX + SR group, or normal saline for MNX + V group. All animals were euthanized 12 weeks later, cartilage degeneration and subchondral bone micro-architecture was analyzed. RESULTS: Both OARSI scores (P = 0.523 for marcoscopic scores, P = 0.297 for histological scores) and Cartilage thickness (P = 0.335) in MNX + SR group were comparable to MNX + V group. However, osteophyte sizes were larger in MNX + SR group (P = 0.014), and collapsed osteophytes in MNX + SR group (7 by 12) were significantly more than in MNX + V group (1 by 12) (P = 0.027), while immunohistochemistry indicates catabolic changes in osteophyte/plateau junction. Micro-CT analysis showed bone mineral density (BMD) (P = 0.001), bone volume fraction (BV/TV) (P = 0.008), trabecular spacing (Tb.Sp) (P = 0.020), trabecular thickness (Tb.Th) (P = 0.012) and structure model index (SMI) (P = 0.005) levels to be significantly higher in the MNX + SR group than in the MNX + V group. CONCLUSIONS: SR (625 mg/kg/day) did not protect cartilage from degeneration in MNX guinea pigs but subchondral bone was significantly enhanced. In early phase OA, SR administration causes osteophyte overgrowth, which may be related to incorporation into mineralizing osteophytes. This adverse effect is important for future studies of SR in OA.

Differences in structural and pain phenotypes in the sodium monoiodoacetate and meniscal transection models of osteoarthritis.

OBJECTIVES: To characterize differences in joint pathology and pain behavior between two rat models of osteoarthritis (OA) in order to inform selection of animal models for interventional studies. METHOD: Knee OA was induced in Sprague Dawley rats by either meniscal transection (MNX) or intra-articular injection of monosodium iodoacetate (MIA). Controls were subjected to sham surgery or saline-injection. In a separate experiment, a single intra-articular injection of triamcinolone acetonide was administered 14 days after MNX or MIA arthritis induction. Pain behavior and joint pathology were quantified. RESULTS: Both models displayed synovial inflammation, chondropathy and osteophytosis. Chondropathy scores increased with time similarly in the two models. Inflammation and osteophyte scores were greater in MNX model compared to the MIA model. At day 49, the MNX model exhibited a greater number of channels crossing the osteochondral junction compared to all other groups. The MNX model exhibited greater weight bearing asymmetry compared to the MIA model, whereas the MIA model displayed more consistent hindpaw allodynia. Triamcinolone attenuated weight bearing asymmetry and distal allodynia to control levels in the MNX model, but distal allodynia was unaltered in the MIA model. CONCLUSIONS: The comparison of the two models of OA in rats, using identical assessment tools has demonstrated that although both models display features of OA, there are differences between the models which may represent different aspects of human OA. Thus, model selection should be based on the pathological aspects of OA under investigation.

Hylan G-F 20 maintains cartilage integrity and decreases osteophyte formation in osteoarthritis through both anabolic and anti-catabolic mechanisms.

OBJECTIVE: To perform a molecular mechanism-based investigation of the chondroprotective potential of hylan G-F 20. METHOD: The effects of hylan G-F 20 on IL-1ß-induced glycosaminoglycan (GAG) depletion and matrix metalloproteinase (MMP) expression in bovine and human cartilage explants were evaluated. Three weekly intra-articular hylan G-F 20 or control injections were administered 4 weeks post-operatively to rabbits with surgically induced osteoarthritis (OA). Cartilage histopathologic scores and osteophyte size were evaluated at 1, 4, and 8 weeks post-injections. Histomorphometry and immunostaining were used to quantify cartilage area and type II collagen (Col II) intensity, and real-time polymerase chain reaction (PCR) was used to examine the mRNA levels of Col2A1, MMP-13, -16 and IL-1ß at 1 week. RESULTS: Hylan G-F 20 retained GAG in IL-1ß-exposed bovine and human cartilage explants and abrogated IL-1ß-mediated increases in MMP-1, -3, and -13 in human explant culture. Hylan G-F 20‒treated OA joints had significantly better cartilage integrity at 1 and 4 weeks post-treatment and significantly smaller osteophytes at 4 weeks compared with control. Col2A1 mRNA increased with hylan G-F 20 treatment, which correlated with a trend toward increased Col II immunostaining. MMP-13 and -16 mRNAs increased in OA cartilage, but were not significantly altered by hylan G-F 20. IL-1ß mRNA was undetectable in cartilage and unaltered in the synovium. CONCLUSIONS: Hylan G-F 20 improved cartilage integrity and decreased osteophyte formation in the rabbit model of OA. Our results suggest that hylan G-F 20 may stimulate cartilage repair by increasing Col II, and inhibit IL-1ß-mediated matrix degradation by decreasing MMPs.

Improvement of nonbullous congenital ichthyosiform erythroderma following functional endoscopic sinus surgery.

We report the case of a child with congenital nonbullous ichthyosiform erythroderma on long-term isotretinoin who developed progressively worsening ichthyosis along with recurrent bouts of sinusitis. Endoscopic sinus surgery revealed osteophytes, most likely an isotretinoin-related adverse event, and post operatively the patient's sinus disease and skin disease both dramatically improved. This case represents the first report, to our knowledge, of ichthyosis improving after endoscopic sinus surgery.