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PubMed2003

[Effects of bisphosphonates on alveolar bone resorption in experimental periodontitis].

Bisphosphonates (BPs) have been successfully used to treat bone diseases such as osteoporosis, Paget's disease of bone, and hypercalcemia of malignancy, which are associated with excessive bone resorption. Periodontitis is also characterized by excessive bone resorption which could lead tooth loss. In this paper, the author described about effects of BPs on alveolar bone resorption in experimental periodontitis, and discussed about the possible use of BPs for the treatment of periodontitis in the clinic.

English Abstract↗

PubMed1987

Synergism between parathyroid hormone and interleukin 1 in stimulating bone resorption in organ culture.

The interaction of interleukin 1 (IL-1), a locally produced factor, and parathyroid hormone (PTH), a systemic factor, in stimulating bone resorption was examined using fetal rat long bone organ culture. Concentrations of IL-1 and PTH, which stimulated little bone resorption when present singly, produced marked resorption when present simultaneously. This synergistic interaction of IL-1 and PTH was not affected by the presence of the prostaglandin synthetase inhibitor indomethacin. Both interleukin 1 alpha and interleukin 1 beta were capable of producing synergy. Synergy was not produced by sequential exposure of bone to IL-1 and PTH, but required the simultaneous presence of both mediators. The leftward shift in the dose response curve of PTH produced by IL-1 may be an important mechanism controlling localized bone resorption. A role for IL-1 in stimulating bone resorption in pathologic conditions, such as arthritis and periodontal disease, is strengthened by the finding that even low concentrations of IL-1 can produce resorptive effects by synergistic interaction with PTH.

Animals↗

PubMed1990

24- and 26-homo-1,25-dihydroxyvitamin D3 analogs: potencies on in vitro bone resorption differ from those reported for cell differentiation.

It has been proposed that the stimulatory effects of 1,25-dihydroxyvitamin D on bone resorption may be mediated through actions on differentiation of marrow cells into monocytic osteoclast precursors. In human promyelocytic leukemia cells (HL-60), 24- and 26-homo-1,25-dihydroxyvitamin D3 and their delta 22 analogs and 24,24-dihomo-1,25-dihydroxyvitamin D3 are 10-fold more potent than 1,25-dihydroxyvitamin D3, and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 is equipotent with 1,25-dihydroxyvitamin D3 in inducing differentiation into the monocytic phenotype. The effect of these 1,25-dihydroxyvitamin D3 analogous on resorption of fetal rat limb bones in vitro was determined in the present study. 1,25-Dihydroxyvitamin D3 was equipotent with 24-homo-1,25-dihydroxyvitamin D3, delta 22-24-homo-1,25-dihydroxyvitamin D3, 26-homo-1,25-dihydroxyvitamin D3, and delta 22-26-homo-1,25-dihydroxyvitamin D3 for in vitro bone resorption, whereas 24,24-dihomo-1,25-dihydroxyvitamin D3 and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 provides evidence to suggest that the mechanism of 1,25-dihydroxyvitamin D3-induced bone resorption may not involve stimulation of monocytic cell differentiation.

Animals↗

PubMed2005

Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease.

UNLABELLED: Inflammatory lesions of periodontal disease contain all the cellular components, including abundant activated/memory T- and B-cells, necessary to control immunological interactive networks and to accelerate bone resorption by RANKL-dependent and -independent mechanisms. Blockade of RANKL function has been shown to ameliorate periodontal bone resorption and other osteopenic disorders without affecting inflammation. Development of therapies aimed at decreasing the expression of RANKL and pro-inflammatory cytokines by T-cells constitutes a promising strategy to ameliorate not only bone resorption, but also inflammation. Several reports have demonstrated that the potassium channels Kv1.3 and IKCa1, through the use of selective blockers, play important roles in T-cell-mediated events, including T-cell proliferation and the production of pro-inflammatory cytokines. More recently, a potassium channel-blocker for Kv1.3 has been shown to down-regulate bone resorption by decreasing the ratio of RANKL-to-OPG expression by memory-activated T-cells. In this article, we first summarize the mechanisms by which chronically activated/memory T-cells, in concert with B-cells and macrophages, trigger inflammatory bone resorption. Then, we describe the main structural and functional characteristics of potassium channels Kv1.3 and IKCa1 in some of the cells implicated in periodontal disease progression. Finally, this review elucidates some recent advances in the use of potassium channel-blockers of Kv1.3 and IKCa1 to ameliorate the clinical signs or side-effects of several immunological disorders and to decrease inflammatory bone resorption in periodontal disease. ABBREVIATIONS: AICD, activation-induced cell death; APC, antigen-presenting cells; B(K), large conductance; CRAC, calcium release-activated calcium channels; DC, dendritic cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN-gamma, interferon-gamma; IP(3), inositol (1,4,5)-triphosphate; (K)ir, inward rectifier; JNK, c-Jun N-terminal kinase; I(K), intermediate conductance; LPS, lipopolysaccharide; L, ligand; MCSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T-cells; RANK, receptor activator of nuclear factor-kappaB; T(CM), central memory T-cells; T(EM), effector memory T-cells; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; OPG, osteoprotegerin; Omp29, 29-kDa outer membrane protein; PKC, protein kinase C; PLC, phospholipase C; RT-PCR, reverse-transcriptase polymerase chain-reaction; S(K), small conductance; TCR, T-cell receptor; and (K)v, voltage-gated.

Alveolar Bone Loss↗

PubMed2000

Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption.

Nitric oxide has been suggested to be involved in the regulation of bone turnover, especially in pathological conditions characterized by release of bone-resorbing cytokines. The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic bone resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role that the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 by studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciotropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Immunohistochemical studies and electrophoretic mobility shift assays performed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NFkappaB and in NFkappaB-DNA binding, which were reversed by treatment with the NO donor S-nitroso-acetyl penicillamine. These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFkappaB in osteoclast precursors.

Animals↗

PubMed2005

Microvascular response in the periosteum following mucoperiosteal flap surgery in dogs: angiogenesis and bone resorption and formation.

BACKGROUND: When surgical stress reaches the periosteum, bone resorption and formation that occur as a periosteal response are closely related to angiogenesis and hemodynamics. Thus, we investigated bone remodeling in the healing process after mucoperiosteal flap surgery, focusing our attention on the microcirculation. METHODS: Mucoperiosteal flap surgery was performed on 12 adult beagle dogs. The periosteal vascular plexus was observed on days 7, 14, 21, and 28 after surgery, using three different techniques: in histological specimens into which India ink was injected into blood vessels, under a light microscope; in ultrathin sections, using a transmission electron microscope; and in acryl plastic-injected vascular corrosion cast specimens, under a scanning electron microscope. RESULTS: On day 7 after surgery, the interstitum of the elevated mucoperiosteal vascular plexus was filled with sinusoidal new blood vessels. Bone resorption by osteoclasts was observed around these new blood vessels and many highly permeable fenestrations were present in the vascular endothelium. On day 14 after surgery, sinusoidal new blood vessels were more markedly developed and some regions exhibited glomeruluslike morphology consistent with bone resorption cavities. Activated osteoblasts were present around these new blood vessels and highly permeable vesicles, which were considered to be possible vesiclo-vacuolar organelles (VVOs) and caveolae, were noted in the vascular endothelium. On days 21 and 28 after surgery, the mucoperiosteal vascular plexus was dissected through regression of endothelial cells and fibroblasts and reconstructed into a rough mesh structure, and simultaneously the bone surface became smooth. CONCLUSION: The morphology of the mucoperiosteal vascular plexus changed with bone metabolism and these changes contributed to transport of substances involved in periodontal repair.

Alveolar Process↗

PubMed1991

Role of prostaglandins in interleukin-1-induced bone resorption in mice in vitro.

The mechanism of bone resorption induced by interleukin 1 (IL-1) was examined in mice using three different in vitro assay systems: a fetal long bone organ culture system, a bone marrow culture system, and a coculture system of primary osteoblastic cell populations and spleen cells. In the organ culture system, recombinant human IL-1 alpha (rhIL-1 alpha) increased both bone resorption and osteoclast number. Both were partially suppressed in the presence of indomethacin. In the marrow culture, both rhIL-1 alpha and rhIL-1 beta stimulated osteoclastlike cell formation, which was completely inhibited by adding indomethacin concurrently. Furthermore, there was a good correlation between the number of osteoclastlike cells formed and the amount of prostaglandin E2 (PGE2) released into the culture media. This indicates that PGE2 is involved in the mechanism of IL-1-mediated osteoclastlike cell formation. In the coculture of primary osteoblastic cell populations and spleen cells, rhIL-1 again stimulated osteoclastlike cell formation, which was inhibited by adding indomethacin. In the cocultures in which direct interaction between osteoblastic cells and spleen cells was inhibited, PGE2 synthesis was similarly increased but no osteoclastlike cells were formed. These results indicate that IL-1 induces osteoclast formation by a mechanism involving PG (most likely PGE2). Furthermore, direct interaction between osteoclast progenitors and osteoblastic cells is required in the osteoclast recruitment induced by IL-1.

Acid Phosphatase↗

PubMed1991

Interleukin-6 does not stimulate bone resorption in neonatal mouse calvariae.

Recombinant human interleukin-6 (IL-6) was assessed for its ability to stimulate bone resorption in prelabeled mouse calvariae in vitro. IL-6 had no effect on bone resorption at concentrations ranging from 300 to 10,000 U/ml (3-1000 pg/ml). Neither the presence of indomethacin nor prolonged incubation periods (96 h) affected this result. IL-6 did not affect resorption stimulated by human recombinant IL-1 alpha (rIL-1 alpha) but inhibited resorption stimulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. rIL-1 alpha, PTH, and 1,25-(OH)2D3 induced IL-6 release by calvariae. We conclude from these studies that IL-6 does not stimulate bone resorption in neonatal mouse calvariae. However, it may act as a locally produced inhibitor and therefore a paracrine regulator of bone resorption induced by osteotropic hormones. IL-6 could also function as a long-range stimulator of systemic reactions and acute-phase responses to local inflammatory and neoplastic lesions in bone.

Animals↗

PubMed2001

Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption.

OPG is a new member of the tumor necrosis factor (TNF) receptor family which plays a key role in the physiological regulation of osteoclastic bone resorption. The protein, which is produced by osteoblasts and marrow stromal cells, lacks a transmembrane domain and acts as a secreted decoy receptor which has no direct signaling capacity. OPG acts by binding to its natural ligand OPGL, which is also known as RANKL (receptor activator of NF-kappaB ligand). This binding prevents OPGL from activating its cognate receptor RANK, which is the osteoclast receptor vital for osteoclast differentiation, activation and survival. Overexpression of OPG in transgenic mice leads to profound osteopetrosis secondary to a near total lack of osteoclasts. Conversely, ablation of the OPG gene causes severe osteoporosis in mice. Ablation of OPGL or RANK also produces profound osteopetrosis, indicating the important physiological role of these proteins in regulating bone resorption. The secretion of OPG and OPGL from osteoblasts and stromal cells is regulated by numerous hormones and cytokines, often in a reciprocal manner. The relative levels of OPG and OPGL production are thought to ultimately dictate the extent of bone resorption. Excess OPGL increases bone resorption, whereas excess OPG inhibits resorption. Recombinant OPG blocks the effects of virtually all factors which stimulate osteoclasts, in vitro and in vivo. OPG also inhibits bone resorption in a variety of animal disease models, including ovariectomy-induced osteoporosis, humoral hypercalcemia of malignancy, and experimental bone metastasis. OPG might represent an effective therapeutic option for diseases associated with excessive osteoclast activity.

Animals↗

PubMed1990

H(+)-stimulated release of prostaglandin E2 and cyclic adenosine 3',5'-monophosphoric acid and their relationship to bone resorption in neonatal mouse calvaria cultures.

The addition of protons to the medium of neonatal mouse calvaria cultures stimulated bone resorption and release of calcium into the medium. In addition, added protons significantly increased the release of prostaglandin E2 (PGE2) and cyclic adenosine 3',5'-monophosphoric acid (cAMP) from the bones. Indomethacin significantly inhibited the release of calcium, PGE2 and cAMP from proton-treated cultures. The positive control, parathyroid hormone (PTH)-treated cultures, also gave rise to bone resorption and calcium release into the medium. However, unlike the addition of protons, the addition of PTH did not stimulate PGE2 release nor did indomethacin inhibit calcium release from PTH-treated cultures. In addition, indomethacin only slightly inhibited cAMP release from PTH-treated cultures, as compared to the marked inhibition by indomethacin of cAMP release from proton-treated cultures. These findings indicate that bone resorption due to added protons is dependent on both PGE2 and cAMP production, whereas bone resorption due to PTH only involves cAMP production.

Animals↗

PubMed1995

Mycotrienins. A new class of potent inhibitors of osteoclastic bone resorption.

Pharmacological intervention using selective tyrosine kinase inhibitors has been shown to be an effective approach to inhibit osteoclast function. Here, we report on the structure-activity relations of benzoquinone ansamycins isolated from Streptomyces rishirensis, which form a new class of potent inhibitors of osteoclast-mediated bone resorption. Parathyroid hormone-stimulated bone resorption was inhibited concentration dependently by both mycotrienin I and mycotrienin II, showing half-maximal inhibition in the low nanomolar range in fetal rat long bones in vitro. Structure-activity relation studies indicate that position 19 contained within the quinone/hydroquinone element and the double bonds in position 4, 6, and 8 are crucial for full bioactivity. In contrast, substitutions in position 22 are well tolerated. The lack of a similar effect of 2,6-dimethyl-p-benzoquinone and vitamin K signifies that the mechanism of action is not solely due to the oxygen scavenger capacity of the quinone/hydroquinone moiety. The inhibition of osteoclastic bone resorption is in line with the diminished activity of immunopurified pp60c-src from bone suggesting that pp60c-src is a possible target of mycotrienins in the organ culture. Thus, mycotrienins may be useful as pharmacologic inhibitors of osteoclastic bone resorption.

Animals↗

PubMed1998

Advances in periodontal diagnosis. 10. Potential markers of bone resorption.

This paper describes the markers of bone resorption which might serve as potential markers for periodontal disease activity. It firstly describes the bone specific proteins which are involved in bone mineralisation and the role they play in this process. It then explains how they may pass into GCF and reviews those studies which have attempted to relate these factors to periodontal disease severity and activity. It next discusses the difficulties in isolating and detecting these factors in GCF and their possible use as markers for periodontal disease activity. As the final part in the series it lastly discusses the possible uses of predictive diagnostic tests of periodontal disease activity in dental practice.

Biomarkers↗

PubMed1980

A revised role for cyclic AMP in prostaglandin-induced bone resorption.

The effect of cyclic AMP on bone resorption produced by prostaglandin E1 (PGE1) and E2 (PGE2) was studied using 6--7 day-old murine calvarial bones cultured in a chemically defined medium for 48 h. Dibutyryl cyclic AMP inhibited in a dose-related way the prostaglandin-induced mobilization of 45Ca from prelabelled bones. The phosphodiesterase inhibitors, theophylline and 3-isobutyl-methylxanthine, also reduced the release of 45Ca induced by the prostaglandins. It was also found that the doses of the later phosphodiesterase inhibitor needed to inhibit prostaglandin-stimulated mineral mobilization were lower than those needed to reduce unstimulated resorption. The mechanism behind the inhibitory effect of cAMP on prostaglandin-induced bone resorption is unknown, but might be related to the capacity of cAMP to inhibit prostaglandin-stimulated release of lysosomal enzymes, which was also demonstrated in this study.

Animals↗

PubMed1995

Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption.

PTH has been postulated to play a role in both nocturnal and age-related increases in bone resorption. We tested this hypothesis directly in 10 young (ages 24-35 yr) and 10 elderly (ages 71-78 yr) normal women by measuring the cross-linked N-telopeptide of type I collagen (NTx), a marker for bone collagen breakdown, in 4-h urine collections before and during suppression of PTH secretion by a 24-h iv infusion of calcium. Serum ionized calcium and PTH levels were also measured every 2 h before and during the infusion. In both groups of women, serum PTH levels and urinary NTx excretion followed a circadian pattern before calcium infusion (analysis of variance, P = 0.0001) with peaks in the afternoon and at night for PTH and at night for urinary NTx. During the calcium infusion, the nocturnal urinary NTx excretion peak persisted (P = 0.0001), despite elimination of both PTH peaks. Urinary 24-h NTx excretion (nanomoles per millimoles of creatinine) at baseline was higher in the elderly women (mean +/- SEM, 25.7 +/- 2.1) than in the young women (19.3 +/- 1.7) (P < 0.01), and the decrease during calcium infusion was greater (7.5 +/- 1.9 vs. 4.1 +/- 1.5, P < 0.05). Therefore, the increase in serum PTH levels with age is one of the major factors responsible for the age-related increase in bone resorption. PTH does not mediate the circadian pattern of bone resorption but does play a role in setting the absolute level of bone resorption at which this pattern occurs.

Adult↗

PubMed1976

Influence of estrogens on bone resorption in organ culture.

Estradiol benzoate, ethinyl estradiol, and human calcitonin were compared for their ability to inhibit the spontaneous or parathyroid extract-induced bone resorption in organ cultures of 19-day fetal rat fibulae. The criteria used for the assessment of bone resorption were: the release of 45Ca from paired prelabeled bone rudiments into the culture medium, the dry weight, and the number of osteoclasts per bone. Estradiol benzoate at concentrations of 1.3 X 10(-5) to 2.6 X 10(-4)M had no effect on the release of 45Ca from fetal fibulae or on the dry weight. Histologically, treated bones were well preserved and resembled the controls. Parathyroid extract (PTE) alone caused extensive bone resorption with numerous osteoclasts and enhanced 45Ca release without weight gain. The addition of estradiol benzoate to the culture medium did not prevent the resorptive action of PTE. Ethinyl estradiol alone provoked a dose-related inhibition of 45Ca release at concentrations of 3.4 X 10(-5) to 1.7 X 10(-4)M. However, this inhibition was accompanied by a decrease in bone dry weight and by various degrees of cellular damage. The same phenomenon was observed in PTE-treated fibulae. Human calcitonin, on the contrary, inhibited the release of 45Ca by decreasing the number of osteoclasts while the weight of the fibulae increased. The inhibitory action of ethinyl estradiol appears to be caused by a toxic effect on bone cells. It is concluded that estrogens have no direct physiological effect on bone resorption in vitro.

Animals↗

PubMed1991

Effects of transforming growth factor-alpha on parathyroid hormone- and parathyroid hormone-related protein-mediated bone resorption and adenylate cyclase stimulation in vitro.

The effects of transforming growth factor-alpha (TGF alpha) were determined on the ability of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) to stimulate bone resorption and adenylate cyclase in vitro. Bovine PTH-(1-34) and human PTHrP-(1-34) were equipotent in their ability to stimulate bone resorption in neonatal mouse calvaria with maximal stimulation (2.9 and 2.8-fold increases in 45Ca release, respectively) at a concentration of 10 nM. Combinations of TGF alpha with bPTH-(1-34) or hPTHrP-(1-34) had additive effects on their ability to stimulate bone resorption when submaximal concentrations of the agonists were used. There was no evidence of synergism between TGF alpha bPTH-(1-34) or hPTHrP-(1-34) in their ability to stimulate bone resorption in vitro, nor was TGF alpha able to increase bone resorption induced by maximal concentrations of bPTH-(1-34) or hPTHrP-(1-34). TGF alpha potentiated the effects of either bPTH-(1-34) or hPTHrP-(1-34) on the stimulation of adenylate cyclase in osteoblast-like ROS 17/2.8 cells. These data indicate that TGF alpha has additive effects with submaximal concentrations of PTH or PTHrP on their ability to stimulate bone resorption which may be important in the pathogenesis of humoral hypercalcemia of malignancy.

Adenylyl Cyclases↗

PubMed1993

Inhibitory effect of ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term cultures of mouse unfractionated bone cells.

To study the effect of ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation, we used an unfractionated bone cell culture system containing mature osteoclasts from femur and tibia of newborn mice. Ipriflavone (10(-5) M) inhibited pit formation on dentin slices and caused a decrease in the number of tartrate-resistant acid phosphatase (TRAP)-positive (+) multinucleate cells (MNCs) in a 4-day culture period in which no increase in the number of TRAP(+)-MNCs was observed in the presence of 5% fetal bovine serum (FBS) and 10(-8) M 1 alpha,25-dihydroxy-vitamin D3 (1 alpha,25(OH)2D3). During the following 12 days, both the total area of the pits and the number of TRAP(+)-MNCs increased in the control. Continuous treatment with ipriflavone also inhibited the increase in pit area during this period. These effects of ipriflavone were reversible. Furthermore, the differentiation of osteoclasts was examined when preexisting TRAP(+)-MNCs were removed by incubation in the absence of 1 alpha,25(OH)2D3 for the initial 4 days in culture dishes without dentin slices. When 1 alpha,25(OH)2D3 and ipriflavone were added to the medium on the 4th day, ipriflavone inhibited new TRAP(+)-MNC formation stimulated by 1 alpha,25(OH)2D3 in a dose-dependent manner. However, pretreatment of the cells with ipriflavone before the addition of 1 alpha,25(OH)2D3 did not inhibit TRAP(+)-MNC formation. These results indicate that ipriflavone inhibits both the activation of mature osteoclasts and the formation of new osteoclasts without affecting growth of TRAP-negative progenitor cells.

Animals↗

PubMed1993

Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo.

Since absence of expression of the c-src gene product in mice indicates that the pp60c-src tyrosine kinase is required and essential for osteoclastic bone resorption, we tested the effects of the antibiotic herbimycin A, which is an inhibitor of pp60c-src on osteoclastic bone resorption in vitro and on hypercalcemia in vivo. We examined the effects of herbimycin A on the formation of bone resorbing osteoclasts in mouse long-term marrow cultures, on isolated rodent osteoclasts and on bone resorption in organ cultures of fetal rat long bones stimulated by parathyroid hormone. We found that herbimycin A in concentrations of 1-100 ng/ml inhibited bone resorption in each of these systems. We determined the effects of herbimycin A (100 ng/ml) on src tyrosine kinase activity in mouse marrow cultures and found that it was decreased. Herbimycin A also decreased elevated blood calcium levels that were induced either by repeated subcutaneous injections of recombinant human interleukin-1 alpha or by a human tumor. There was no evidence for toxicity in any of these culture systems or in mice treated with herbimycin A. A different tyrosine kinase inhibitor that does not inhibit pp60c-src was used as a control and caused none of these effects. These data suggest that pp60c-src tyrosine kinase inhibitors may be useful pharmacologic inhibitors of osteoclastic bone resorption and hypercalcemia.

Animals↗