Doxercalciferol Alleviates Bone Deteriorations and Cartilage Degeneration in Aging Mice

Abstract

Background Age-related bone deteriorations are the common endocrine disorders in the elderly population, leading to an increased risk of fractures. Therefore, effective treatment strategies provide a way to prevent bone loss and improve the quality of life in the elderly population. The present study aimed to investigate the anti-osteoporotic effects of doxercalciferol (DOX) in aging mice.

Methods Bone metabolism-related markers were measured by ELISA assay. The expression of bone formation and resorption-related genes was performed by RT-qPCR analysis. Hematoxylin and eosin (H&E) and Safranin O staining were performed to analyze the trabecular bone and cartilage degeneration.

Results Aging resulted in urine ca²⁺ excretion, a decrease in bone ca²⁺ content and reduction of biomechanical strength in mice. We also found that the level of PTH was increased in aging mice, while DOX administration markedly down-regulated serum PTH in aging mice. H&E and Safranin O staining showed that DOX protected against aging-induced bone loss and cartilage regeneration in the tibia from aging mice. Furthermore, DOX treatment resulted in an increase in Runx2, osterix and Col1a1 mRNA expression and a decrease in Ctsk, MMP-9 and CAII mRNA expression in the tibia from aging mice.

Conclusion These findings indicated that DOX had a beneficial effect on age-related bone deteriorations in aging mice by promoting osteoblast activity and cartilage regeneration and inhibiting osteoclast-specific genes expression.

Key words

doxercalciferol - osteoporosis - aging - skeleton - PTH

Publication History

Received: 03 July 2018
Received: 27 July 2018

Accepted: 03 October 2018

Article published online:
31 October 2018

• References

• 1 Mayhew PM, Thomas CD, Clement JG. et al. Relation between age, femoral neck cortical stability, and hip fracture risk. Lancet (London, England) 2005; 366: 129-135
• 2 Gosch M, Kammerlander C, Nicholas JA. Treatment of osteoporosis in older adults. Panminerva medica 2014; 56: 133-143
• 3 Johnell O. The socioeconomic burden of fractures: Today and in the 21^st century. The American journal of medicine 1997; 103: 20S-25S discussion 25S-26S
• 4 Plotkin LI, Laird DW, Amedee J. Role of connexins and pannexins during ontogeny, regeneration, and pathologies of bone. BMC cell biology 2016; 17 (Suppl. 01) 19
• 5 Bidwell JP, Alvarez MB, Hood Jr. M. et al. Functional impairment of bone formation in the pathogenesis of osteoporosis: The bone marrow regenerative competence. Current osteoporosis reports 2013; 11: 117-125
• 6 Ray K. Doxercalciferol is as effective as calcitriol for the treatment of secondary hyperparathyroidism in CKD. Nature reviews Nephrology 2010; 6: 692
• 7 Wesseling-Perry K, Pereira RC, Sahney S. et al. Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. Kidney international 2011; 79: 112-119
• 8 Moe SM, Saifullah A, LaClair RE. et al. A randomized trial of cholecalciferol versus doxercalciferol for lowering parathyroid hormone in chronic kidney disease. Clinical journal of the American Society of Nephrology : CJASN 2010; 5: 299-306
• 9 Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Current opinion in pharmacology 2015; 22: 41-50
• 10 Kim JH, Kim AR, Choi YH. et al. Intermittent PTH administration improves alveolar bone formation in type 1 diabetic rats with periodontitis. Journal of translational medicine 2018; 16: 70
• 11 Huang JC, Sakata T, Pfleger LL. et al. PTH differentially regulates expression of RANKL and OPG. Journal of bone and mineral research : The official journal of the American Society for Bone and Mineral Research 2004; 19: 235-244
• 12 Li XL, Wang L, Bi XL. et al. Gushukang exerts osteopreserve effects by regulating vitamin D and calcium metabolism in ovariectomized mice. Journal of bone and mineral metabolism 2018;
• 13 Hou HT, Wang YN, Shao SZ. et al. High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice. Experimental and therapeutic medicine 2018; 15: 3483-3488
• 14 Flicker L, Lichtenstein M, Colman P. et al. The effect of aging on intact PTH and bone density in women. Journal of the American Geriatrics Society 1992; 40: 1135-1138
• 15 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif) 2001; 25: 402-408
• 16 Silva BC, Costa AG, Cusano NE. et al. Catabolic and anabolic actions of parathyroid hormone on the skeleton. Journal of endocrinological investigation 2011; 34: 801-810
• 17 Coburn JW, Maung HM, Elangovan L. et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. American journal of kidney diseases: The official journal of the National Kidney Foundation 2004; 43: 877-890
• 18 Hirai T, Kobayashi T, Nishimori S. et al. Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis. Endocrinology 2015; 156: 2774-2780
• 19 Pasch A, Frey FJ, Eisenberger U. et al. PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers. Nephrology, dialysis, transplantation: Official publication of the European Dialysis and Transplant Association - European Renal Association 2008; 23: 2563-2570
• 20 Parisi MS, Oliveri B, Somoza J. et al. Effect of doxercalciferol (1alpha-hydroxyvitamin D2) on PTH, bone turnover and bone mineral density in a hemodialysis patient with persistent secondary hyperparathyroidism post parathyroidectomy. Clinical nephrology 2003; 59: 471-474
• 21 Gu SS, Zhang Y, Li XL. et al. Involvement of the skeletal renin-angiotensin system in age-related osteoporosis of ageing mice. Bioscience, biotechnology, and biochemistry 2012; 76: 1367-1371
• 22 Shahnazari M, Dwyer D, Chu V. et al. Bone turnover markers in peripheral blood and marrow plasma reflect trabecular bone loss but not endocortical expansion in aging mice. Bone 2012; 50: 628-637
• 23 Blaney Davidson EN, Scharstuhl A, Vitters EL. et al. Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity. Arthritis research & therapy 2005; 7: R1338-R1347
• 24 Mort JS, Beaudry F, Theroux K. et al. Early cathepsin K degradation of type II collagen in vitro and in vivo in articular cartilage. Osteoarthritis and cartilage 2016; 24: 1461-1469
• 25 Kozawa E, Cheng XW, Urakawa H. et al. Increased expression and activation of cathepsin K in human osteoarthritic cartilage and synovial tissues. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 2016; 34: 127-134
• 26 Svelander L, Erlandsson-Harris H, Astner L. et al. Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice. European journal of pharmacology 2009; 613: 155-162
• 27 Collins FL, Williams JO, Bloom AC. et al. CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss. Bone 2017; 97: 94-104
• 28 Kogawa M, Wijenayaka AR, Ormsby RT. et al. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. Journal of bone and mineral research: The official journal of the American Society for Bone and Mineral Research 2013; 28: 2436-2448
• 29 Zhang Z, Song C, Fu X. et al. High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio. International journal of molecular sciences 2014; 15: 17130-17147