Endocrinol Metab.  2013 Dec;28(4):255-261. 10.3803/EnM.2013.28.4.255.

Recent Progress in Osteocyte Research

• Divieti Pajevic P

• KMID: 2169302
• DOI: http://doi.org/10.3803/EnM.2013.28.4.255

Abstract

The last decade has seen an exponential increase in our understanding of osteocytes function and biology. These cells, once considered inert by-standers trapped into the mineralized bone, has now risen to be key regulators of skeletal metabolism, mineral homeostasis, and hematopoiesis. As tools and techniques to study osteocytes improved and expanded, it has become evident that there is more to these cells than initially thought. Osteocytes are now recognized not only as the key responders to mechanical forces but also as orchestrators of bone remodeling and mineral homeostasis. These cells are the primary source of several important proteins, such as sclerostin and fibroblast growth factor 23, that are currently target as novel therapies for bone loss (as the case for antisclerostin antibodies) or phosphate disorders. Better understanding of the intricate cellular and molecular mechanisms that govern osteocyte biology will open new avenue of research and ultimately indentify novel therapeutics to treat bone and mineral disorders. This review summarizes novel findings and discusses future avenues of research.

Keyword

Osteocytes; Sclerostin; Mineral homeostasis; Bone homeostasis

MeSH Terms

Biology
Bone Remodeling
Fibroblast Growth Factors
Hematopoiesis
Homeostasis
Metabolism
Osteocytes*
Fibroblast Growth Factors

Reference

1. Gaillard PJ, Talmage RV, Budy AM, te Leiden R. Rice University. Osteolysis: an outlook on its mechanism and causation. The parathyroid glands: ultrastructure, secretion, and function. Chicago: University of Chicago Press;1965. p. 137–143.

2. Rutishauser E, Majno G. Physiopathology of bone tissue; the osteocytes and fundamental substance. Bull Hosp Joint Dis. 1951; 12:469–490. PMID: 14905125.

3. Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011; 26:229–238. PMID: 21254230.

4. Zhang K, Barragan-Adjemian C, Ye L, Kotha S, Dallas M, Lu Y, Zhao S, Harris M, Harris SE, Feng JQ, Bonewald LF. E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation. Mol Cell Biol. 2006; 26:4539–4552. PMID: 16738320.

5. Kalajzic I, Matthews BG, Torreggiani E, Harris MA, Divieti Pajevic P, Harris SE. In vitro and in vivo approaches to study osteocyte biology. Bone. 2013; 54:296–306. PMID: 23072918.

6. Windahl SH, Borjesson AE, Farman HH, Engdahl C, Moverare-Skrtic S, Sjogren K, Lagerquist MK, Kindblom JM, Koskela A, Tuukkanen J, Divieti Pajevic P, Feng JQ, Dahlman-Wright K, Antonson P, Gustafsson JA, Ohlsson C. Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice. Proc Natl Acad Sci U S A. 2013; 110:2294–2299. PMID: 23345419.

7. Marotti G, Ferretti M, Remaggi F, Palumbo C. Quantitative evaluation on osteocyte canalicular density in human secondary osteons. Bone. 1995; 16:125–128. PMID: 7742070.

8. Palumbo C, Palazzini S, Marotti G. Morphological study of intercellular junctions during osteocyte differentiation. Bone. 1990; 11:401–406. PMID: 2078434.

9. Palumbo C, Palazzini S, Zaffe D, Marotti G. Osteocyte differentiation in the tibia of newborn rabbit: an ultrastructural study of the formation of cytoplasmic processes. Acta Anat (Basel). 1990; 137:350–358. PMID: 2368590.

10. Schweitzer MH, Wittmeyer JL, Horner JR, Toporski JK. Soft-tissue vessels and cellular preservation in Tyrannosaurus rex. Science. 2005; 307:1952–1955. PMID: 15790853.

11. Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell.And more. Endocr Rev. 2013; 34:658–690. PMID: 23612223.

12. Price C, Zhou X, Li W, Wang L. Real-time measurement of solute transport within the lacunar-canalicular system of mechanically loaded bone: direct evidence for load-induced fluid flow. J Bone Miner Res. 2011; 26:277–285. PMID: 20715178.

13. Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007; 5:464–475. PMID: 17550781.

14. Jacobs CR, Temiyasathit S, Castillo AB. Osteocyte mechanobiology and pericellular mechanics. Annu Rev Biomed Eng. 2010; 12:369–400. PMID: 20617941.

15. Temiyasathit S, Tang WJ, Leucht P, Anderson CT, Monica SD, Castillo AB, Helms JA, Stearns T, Jacobs CR. Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. PLoS One. 2012; 7:e33368. PMID: 22428034.

16. Xiao Z, Dallas M, Qiu N, Nicolella D, Cao L, Johnson M, Bonewald L, Quarles LD. Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J. 2011; 25:2418–2432. PMID: 21454365.

17. Xiao Z, Zhang S, Mahlios J, Zhou G, Magenheimer BS, Guo D, Dallas SL, Maser R, Calvet JP, Bonewald L, Quarles LD. Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J Biol Chem. 2006; 281:30884–30895. PMID: 16905538.

18. Gluhak-Heinrich J, Ye L, Bonewald LF, Feng JQ, MacDougall M, Harris SE, Pavlin D. Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo. J Bone Miner Res. 2003; 18:807–817. PMID: 12733719.

19. Harris SE, Gluhak-Heinrich J, Harris MA, Yang W, Bonewald LF, Riha D, Rowe PS, Robling AG, Turner CH, Feng JQ, McKee MD, Nicollela D. DMP1 and MEPE expression are elevated in osteocytes after mechanical loading in vivo: theoretical role in controlling mineral quality in the perilacunar matrix. J Musculoskelet Neuronal Interact. 2007; 7:313–315. PMID: 18094489.

20. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008; 283:5866–5875. PMID: 18089564.

21. Spatz JM, Ellman R, Cloutier AM, Louis L, van Vliet M, Suva LJ, Dwyer D, Stolina M, Ke HZ, Bouxsein ML. Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J Bone Miner Res. 2013; 28:865–874. PMID: 23109229.

22. Frost HM. Bone "mass" and the "mechanostat": a proposal. Anat Rec. 1987; 219:1–9. PMID: 3688455.

23. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013; 19:179–192. PMID: 23389618.

24. Bergwitz C, Juppner H. FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol. 2012; 728:41–64. PMID: 22396161.

25. Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010; 61:91–104. PMID: 20059333.

26. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011; 17:1231–1234. PMID: 21909105.

27. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med. 2011; 17:1235–1241. PMID: 21909103.

28. Onal M, Piemontese M, Xiong J, Wang Y, Han L, Ye S, Komatsu M, Selig M, Weinstein RS, Zhao H, Jilka RL, Almeida M, Manolagas SC, O'Brien CA. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem. 2013; 288:17432–17440. PMID: 23645674.

29. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006; 38:1310–1315. PMID: 17033621.

30. Sheng MH, Zhou XD, Bonewald LF, Baylink DJ, Lau KH. Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. Bone. 2013; 52:133–144. PMID: 23032105.

31. Cullinane DM. The role of osteocytes in bone regulation: mineral homeostasis versus mechanoreception. J Musculoskelet Neuronal Interact. 2002; 2:242–244. PMID: 15758444.

32. Tazawa K, Hoshi K, Kawamoto S, Tanaka M, Ejiri S, Ozawa H. Osteocytic osteolysis observed in rats to which parathyroid hormone was continuously administered. J Bone Miner Metab. 2004; 22:524–529. PMID: 15490261.

33. Lane NE, Yao W, Balooch M, Nalla RK, Balooch G, Habelitz S, Kinney JH, Bonewald LF. Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res. 2006; 21:466–476. PMID: 16491295.

34. Qing H, Ardeshirpour L, Pajevic PD, Dusevich V, Jahn K, Kato S, Wysolmerski J, Bonewald LF. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res. 2012; 27:1018–1029. PMID: 22308018.

35. Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Pajevic PD. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol. 2011; 209:21–32. PMID: 21220409.

36. Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, Lafage-Proust MH, Dresselaers T, Feng JQ, Bonewald LF, Meyer MB, Pike JW, Bouillon R, Carmeliet G. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest. 2012; 122:1803–1815. PMID: 22523068.

37. Krause DS, Scadden DT. Deconstructing the complexity of a microenvironmental niche. Cell. 2012; 149:16–17. PMID: 22464318.

38. Krause DS, Scadden DT, Preffer FI. The hematopoietic stem cell niche: home for friend and foe? Cytometry B Clin Cytom. 2013; 84:7–20. PMID: 23281119.

39. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425:841–846. PMID: 14574413.

40. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425:836–841. PMID: 14574412.

41. Wu JY, Purton LE, Rodda SJ, Chen M, Weinstein LS, McMahon AP, Scadden DT, Kronenberg HM. Osteoblasticregulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways. Proc Natl Acad Sci U S A. 2008; 105:16976–16981. PMID: 18957542.

42. Rankin EB, Wu C, Khatri R, Wilson TL, Andersen R, Araldi E, Rankin AL, Yuan J, Kuo CJ, Schipani E, Giaccia AJ. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012; 149:63–74. PMID: 22464323.

43. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, Tesio M, Samstein RM, Goichberg P, Spiegel A, Elson A, Lapidot T. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006; 12:657–664. PMID: 16715089.

44. Calvi LM, Bromberg O, Rhee Y, Weber JM, Smith JN, Basil MJ, Frisch BJ, Bellido T. Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells. Blood. 2012; 119:2489–2499. PMID: 22262765.

45. Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, Lotinun S, Baron R, Bonewald L, Feng JQ, Chen M, Weinstein LS, Wu JY, Kronenberg HM, Scadden DT, Divieti Pajevic P. Myelopoiesis is regulated by osteocytes through Gsα-dependent signaling. Blood. 2013; 121:930–939. PMID: 23160461.

46. Cain CJ, Rueda R, McLelland B, Collette NM, Loots GG, Manilay JO. Absence of sclerostin adversely affects B-cell survival. J Bone Miner Res. 2012; 27:1451–1461. PMID: 22434688.