Inhibition of bone resorption blunts osteoarthritis in mice with high bone remodelling.

BACKGROUND: Osteoarthritis (OA) is characterised by cartilage degradation and bone lesions. Subchondral bone may be involved in the pathogenesis of cartilage matrix breakdown. OBJECTIVE: To assess the role of bone remodelling in OA by studying the effect of bisphosphonate on OA development in mice with high bone remodelling. METHODS: Mice overexpressing Runx2 (Runx2-Tg) under the control of collagen type I that displayed high bone remodelling were used. Joint instability was performed by partial medial meniscectomy to induce OA. RESULTS: Six weeks after surgery, tibial cartilage of Runx2-Tg mice displayed an increased number of ADAMTS-4- and ADAMTS-5-expressing chondrocytes compared with controls (p<0.05). This increase was higher in Runx2-Tg mice than in wild-type mice, although their OA score did not differ (2.5+/-0.6 vs 2.4+/-0.2, P=NS). Pamidronate reduced the OA score in Runx2-Tg mice but not in wild-type littermates (1.2+/-0.5 vs 2.7+/-0.4; p<0.05) despite the reduction of bone resorption and of the expression of cartilage proteases in both genotypes. CONCLUSIONS: These findings support the hypothesis that the level of bone resorption influences cartilage metabolism and that inhibition might prevent the progression of OA. Targeting bone resorption might therefore provide an approach to the treatment of high bone resorbing forms of OA.

Estradiol and raloxifene decrease the formation of multinucleate cells in human bone marrow cultures.

Estrogen (E2) deficiency is responsible for increased bone turnover in the postmenopausal period, and it can be prevented by estrogen replacement therapy. The way estrogen acts on bone cells is not fully understood. Human bone marrow cell cultures may be a reliable model for studying the action of steroids on osteoclastogenesis in vitro. We examine the effects of estradiol and Raloxifene, a selective estrogen receptor modulator, on human primary bone marrow cells cultured for 15 days. 17beta-estradiol and Raloxifene significantly decreased the number of tartrate-resistant acid phosphatase multinucleate cells from osteoclast precursors on day 15. Estrogen receptor alpha (ER-alpha) mRNA was present in bone marrow mononuclear cells cultured for 5 days, but there was no estrogen receptor beta (ER-beta) mRNA, suggesting that this effect was mediated by ER-alpha. 15-day cultures no longer contained ER-alpha mRNA, suggesting that estrogen acts on early events of osteoclast differentiation. Finally, 10-8 M 17beta-estradiol has no effect on the release of IL-6 and IL-6-sr into the medium of marrow mononuclear cells cultured for 5 or 15 days. Osteoclast apoptosis was not affected by estradiol or Raloxifene after 15 days of culture under our conditions. In conclusion, we have shown that both estradiol and Raloxifene inhibit osteoclast differentiation in human bone marrow mononuclear cultures. The biological effect that can mimic in vivo differentiation could be mediated through ER-alpha.

Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients.

BACKGROUND: Osteomalacia is now a rare disease in dialysis patients in developed countries since the withdrawal of aluminium overload. The involvement of fluoride and strontium in the pathogenesis of the disease has been suggested. The aim of this study was to investigate a possible association between osteomalacia in dialysis patients and the fluoride or strontium contents of bone. METHODS: Of 271 bone biopsies from chronic haemodialysis patients referred to our centre, we studied the nine biopsies from patients with osteomalacia. They were compared with 23 biopsies from patients with hyperparathyroidism and 24 biopsies from patients with adynamic bone disease. Histomorphometric static and dynamic indices were measured. Bone fluoride and strontium contents were measured in biopsies from haemodialysis patients, and were compared with those of control patients. RESULTS: In the nine patients with osteomalacia, we found an absence of double labelled surfaces and increased osteoid thickness. Mild aluminium overload was observed in two of the nine patients. The bone strontium content of the entire dialysis population studied was not significantly different from control values (0.023+/-0.001 vs 0.019+/-0.002% mol/mol, P=0.15). However, bone strontium level was slightly but significantly increased in patients with osteomalacia (0.030+/-0.005%), compared with both controls (0.019+/-0.002%, P<0.05) and the other bone diseases (0.021+/-0.002%, P<0.05). Bone fluoride content was significantly higher in the entire dialysis population than in the controls (0.33+/-0.04 vs 0.13+/-0.018% (g/g ash weight), P=0.04). It was increased in osteomalacic patients compared with controls and with patients having hyperparathyroidism or adynamic bone disease. There was no correlation between formation indices (OV/BV, OS/BS, Ob.S/BS) and bone fluoride or strontium content. CONCLUSIONS: We found a prevalence of osteomalacia of 3.3% in our biopsy series for chronic dialysis patients. However, although bone strontium and fluoride contents were slightly increased, no causal relationship with these individual metals and osteomalacia could be firmly established in this small number of patients. The hypothesis of strontium- or fluoride-induced osteomalacia in renal patients merits further investigation.

Porque estrógeno e raloxifeno melhoram a densidade mineral ossea? mecanismos de açäo do estrógeno e de um modulador seletivo do receptor de estrógeno (SERM) no osso / Why estrogen and raloxifene improve the bone mineral density? action mechanisms of estrogen and of a selective estrogen receptor modulator (SERM) in bone

A deficiência de estrógeno é responsável pelo aumento na remodelaçäo óssea após a menopausa, cuja prevençäo é feita pela terapia de reposiçäo hormonal com estrógeno; porém, ainda näo está esclarecido o mecanismo da açäo anti-reabsortiva do estrógeno no osso e permanecem várias questöes: (1) Qual a célula-alvo de açäo do estrógeno no osso? O receptor de estrógeno já foi descrito em monócito, osteoclasto, célulacs do estroma da medula óssea e osteoblasto, mas é desconhecido o papel dessas célulacs no efeito do estrógeno. (2) Quais os mediadores do efeito do estrógeno no osso? Os resultados da literatura säo controversos quanto ao papel da interleucina-6, sendo a maioria dos resultados positivos em animais e näo no homem. Outras citoquinas como interleucina-1 e fator de necrose tumoral parecem estar envolvidos. (3) O efeito anti-osteoclástico do estrógeno está relacionado à apoptose de precursores dos osteoclastos? Já foi relatado em animais, que o estrógeno aumenta apoptose dos precursores dos osteoclastos, porém näo é conhecido ese efeito no homem. (4) Qual o papel do estroma na medula óssea na osteoclastogênese e na sua inibiçäo pelo estrógeno? Recentemente foi descrito um fator, produzido pelas células do estroma (RANK ligante) que induz a formaçäo de osteoclasto, sugerindo a importância dessas células na osteoclastogênese e no efeito do estrógeno no osso. (5) Qual a via de transcriçäo intracelular do efeito do estrógeno? Proteínas NF-kB podem ter um papel significante na osteoporose pós-menopausa, podendo corresponder à via pelo qual o estrógeno regula a produçäo de citoquinas envolvidas na osteoclastogênese, porém ainda näo está esclarecido este efeito. Estas questöes, sobre o mecanismo de açäo do estrógeno, como tammbém dos SERMs seräo discutidas nessa revisäo.