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Lawrence Raisz

Publications and source records attributed to Lawrence Raisz.

6 recordsLinked to original sources
PubMed2006

Impact of smoking cessation on bone mineral density in postmenopausal women.

BACKGROUND: Although clinical guidelines recommend smoking cessation to improve bone health, the impact of short-term smoking cessation (i.e., 1 year) on bone mineral density (BMD) is not known. We examined the effects of smoking cessation on BMD measurements, markers of bone turnover, and hormone profiles in postmenopausal women. METHODS: Postmenopausal women (n = 152) who smoked at least 10 cigarettes per day were randomly assigned to behavioral counseling and either nicotine or placebo patch for smoking cessation (3-month treatment with a 1-month taper) and followed for an additional year. The BMD at various sites (hip, spine, wrist, and total body), serum and urine biochemical markers of bone turnover, and sex hormones were measured at baseline and again 1 year after smoking treatment. Women who continuously abstained from smoking between the end of treatment and 1 year later (quitters) (n = 42) were compared with women who completed the study and continued to smoke (n = 77). RESULTS: Femoral trochanter BMD increased by 2.9% among quitters vs. 0.6% among continued smokers (p = 0.02). Total hip BMD increased by 1.52% among quitters vs. 0.43% among continued smokers (p = 0.03). Changes in BMD at the femoral neck, radius, spine, and total body did not significantly differ between groups. The effects of smoking cessation on bone were mediated in part by weight gain. Smoking cessation was also associated with an increase in bone alkaline phosphatase. CONCLUSIONS: Smoking cessation, relative to continued smoking, increases BMD at the femoral trochanter and total hip in postmenopausal women.

Absorptiometry, Photon↗
PubMed2004

Do cyclooxygenase-2 knockout mice have primary hyperparathyroidism?

The absence of cyclooxygenase-2 (COX-2) activity in vitro reduces differentiation of both bone-forming and bone-resorbing cells. To examine the balance of COX-2 effects on bone in vivo, we studied COX-2 knockout (KO) and wild-type (WT) mice. After weaning, KO mice died 4 times faster than WT mice, consistent with reports of progressive renal failure in KO mice. Among KO mice killed at 4 months of age, some had renal failure with marked secondary hyperparathyroidism, but others appeared healthy. On the assumption that renal failure was not inevitable in COX-2 KO mice and that phenotypic differences might increase with age, we studied KO mice surviving to 10 months of age with serum creatinine levels similar to those of WT mice. In 10-month-old male KO mice, serum calcium and PTH, but not phosphorus, levels were increased compared with those in WT mice. 1,25-Dihydroxyvitamin D(3) levels were markedly elevated in KO mice. Skeletal analysis showed small nonsignificant decreases in cortical bone density by BMD and either an increase (distal femur, by microcomputed tomography) or no difference (distal femur, by static histomorphometry) in trabecular bone density in KO mice. There was a trend toward increased percent osteoblastic and osteoclastic surfaces, and on dynamic histomorphometry, the rates of trabecular bone formation and mineral apposition were increased in KO mice relative to WT mice. Similar trends were observed for most parameters in 10-month-old female COX-2 KO mice. However, rates of trabecular bone formation and mineral apposition were increased in 10-month-old WT females compared with males and did not increase further in female KO mice. These data suggest that COX-2 KO mice with intact renal function have primary hyperparathyroidism, and that effects of increased PTH and 1,25-dihydroxyvitamin D(3) to increase bone turnover may compensate for the absence of COX-2.

Animals↗
PubMed2003

Role of cyclooxygenase-2 in bone resorption.

Prostaglandins (PGs) are abundant in bone and are potent regulators of bone cell function. Osteoblasts produce PGs, and this production is highly regulated by local and systemic factors. Bone resorption is a highly regulated process involving interactions of osteoclastic precursors with osteoblasts or stromal cells. Many factors that stimulate PGs production also stimulate resorption in organ and marrow culture. Cyclooxygenase (COX) is the rate-limiting enzyme in the conversion of arachidonic acid to PGs. There are two forms of COX, COX-1 and COX-2. COX-2 is an inducible primary-response or immediate early gene. COX-2 expression is induced by many factors through the transcriptional pathway in osteoblasts. Stimulated production of PGs by osteoblasts requires both the induction of COX-2 expression and the availability of arachidonic acid substrate. PGs are complex, potent regulators of bone cell function in vivo. PGE2, which may be the most important local eicosanoid in skeletal regulation, can stimulate resorption. We report that COX-2 expression and associated PG production are necessary for maximal resorption responses to 1,25 (OH)2D3 and parathyroid hormone (PTH). PGs can increase osteoclast formation by enhancing induction of the receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts and enhancing the action of RANKL on osteoclast precursors by inhibiting granulocyte macropharge-colony stimulating factor (GM-CSF). In vitro, PGE2 can stimulate the differentiation of both osteoblasts and osteoclasts, and the net balance of these two effects under physiologic or pathologic conditions in vivo is not yet clear. Our in vivo data suggest that a role for COX-2 in bone resorption may be most evident when bone resorption is accelerated. Some of the complexity of PG actions on bone can be explained by the multiplicity of receptors for PGs. There are at least four distinct receptors for PGE2 with differential signaling pathways that have not yet been fully elucidated. Further studies are needed to clarify the specific pathways of PGs action in bone. Once this is accomplished, it may be possible to identify therapeutic applications of manipulating PGs in skeletal disorders.

Animals↗
PubMed2002

Fluid flow induces COX-2 expression in MC3T3-E1 osteoblasts via a PKA signaling pathway.

Mechanical loading of bone generates fluid flow within the mineralized matrix which can exert fluid shear stress (FSS) at cell membranes. FSS induces new transcription of cyclooxygenase-2 (COX-2) in MC3T3-E1 osteoblasts, with peak effects at 4-5h. Using MC3T3-E1 cells stably transfected with the COX-2 promoter fused to a luciferase reporter, we examined involvement of the protein kinase A (PKA) and protein kinase C (PKC) signaling pathways in the peak COX-2 mRNA and luciferase responses to FSS (10dyn/cm(2)). Neither inhibition nor down-regulation of the PKC pathway affected the FSS stimulation of COX-2 mRNA or luciferase activity. In contrast, inhibitors of the PKA pathway, used at doses which inhibited forskolin-stimulated luciferase activity by 70-80%, reduced FSS-stimulated COX-2 mRNA expression and luciferase activity by 50-80%. Hence, peak FSS induction of COX-2 expression in MC3T3-E1 osteoblastic cells is largely dependent on the PKA signaling pathway.

Animals↗
PubMed2002

Cell-to-Cell adhesion via intercellular adhesion molecule-1 and leukocyte function-associated antigen-1 pathway is involved in 1alpha,25(OH)2D3, PTH and IL-1alpha-induced osteoclast differentiation and bone resorption.

Cell-to-cell interaction is required for the differentiation of osteoclast precursors as well as for osteoclast function. The present study was undertaken to determine whether 1,25 dihydroxyvitamin D3 (1,25D), PTH, IL-1alpha and PGE2 depend on cell-to-cell interactions through the intercellular adhesion molecule (ICAM)-1/leukocyte function-associated antigen (LFA)-1 pathway in osteoclast formation and bone resorption. We found that mouse osteoblasts expressed ICAM-1 and that the expression was increased by treatment with PTH, IL-1alpha or 1,25D, but not by PGE2. In resorption assays measuring either 45Ca release from bone organ cultures or pit formation in bone cell cultures, 1,25D-, PTH- and IL-1alpha-stimulated resorption was inhibited by anti-ICAM-1 monoclonal antibody (mAb) and/or anti-LFA-1 mAb, while basal and PGE2-stimulated bone resorbing activities were not affected by these mAbs. Furthermore, in a mouse bone marrow culture system, stimulation of osteoclast-like (OCL) cell formation by 1,25D (10 nM), PTH (10 ng/ml) or IL-1alpha (10 ng/ml) was inhibited by the addition of anti-ICAM-1 mAb and/or anti-LFA-1 mAb. In a coculture system of murine spleen cells and osteoblasts, the ICAM-1/LFA-1 interaction was also involved in 1,25D-, PTH- and IL-1alpha-stimulated TRAP-positive MNC formation. However, anti-ICAM-1 mAb and anti-LFA-1 mAb did not alter either 1,25D- or PTH-stimulated receptor activator of NF-kappaB ligand (RANKL) mRNA transcription in bone marrow cultures. Taken together, we here propose that ICAM-1-mediated cell-to-cell adhesion of osteoblasts and osteoclast precursors is involved in RANKL-dependent osteoclast maturation stimulated by 1,25D, PTH, and IL-1alpha.

Animals↗