Sclerostin Modulates Mineralization Degree and Stiffness Profile in the Fibrocartilaginous Enthesis for Mechanical Tissue Integrity

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2024 Jun 19

PMID 38895158

Authors

Shinsei Yambe

Yuki Yoshimoto

Kazutaka Ikeda

Koichiro Maki

Aki Takimoto

Akihide Tokuyama

Shinnosuke Higuchi

Xinyi Yu

Kenta Uchibe

Shigenori Miura

Hitomi Watanabe

Tetsushi Sakuma

Takashi Yamamoto

Kotaro Tanimoto

Gen Kondoh

Masataka Kasahara

Toshihide Mizoguchi

Denitsa Docheva

Taiji Adachi

Chisa Shukunami

Affiliations

Soon will be listed here.

Abstract

Fibrocartilaginous entheses consist of tendons, unmineralized and mineralized fibrocartilage, and subchondral bone, each exhibiting varying stiffness. Here we examined the functional role of sclerostin, expressed in mature mineralized fibrochondrocytes. Following rapid mineralization of unmineralized fibrocartilage and concurrent replacement of epiphyseal hyaline cartilage by bone, unmineralized fibrocartilage reexpanded after a decline in alkaline phosphatase activity at the mineralization front. Sclerostin was co-expressed with osteocalcin at the base of mineralized fibrocartilage adjacent to subchondral bone. In -deficient mice with less mechanical loading due to defects of the Achilles tendon, sclerostin fibrochondrocyte count significantly decreased in the defective enthesis where chondrocyte maturation was markedly impaired in both fibrocartilage and hyaline cartilage. Loss of the gene, encoding sclerostin, elevated mineral density in mineralized zones of fibrocartilaginous entheses. Atomic force microscopy analysis revealed increased fibrocartilage stiffness. These lines of evidence suggest that sclerostin in mature mineralized fibrochondrocytes acts as a modulator for mechanical tissue integrity of fibrocartilaginous entheses.

References

Benjamin M, Toumi H, Ralphs J, Bydder G, Best T, Milz S . Where tendons and ligaments meet bone: attachment sites ('entheses') in relation to exercise and/or mechanical load. J Anat. 2006; 208(4):471-90. PMC: 2100202. DOI: 10.1111/j.1469-7580.2006.00540.x. View

Yoshimoto Y, Takimoto A, Watanabe H, Hiraki Y, Kondoh G, Shukunami C . Scleraxis is required for maturation of tissue domains for proper integration of the musculoskeletal system. Sci Rep. 2017; 7:45010. PMC: 5361204. DOI: 10.1038/srep45010. View

Ichijo R, Maki K, Kabata M, Murata T, Nagasaka A, Ishihara S . Vasculature atrophy causes a stiffened microenvironment that augments epidermal stem cell differentiation in aged skin. Nat Aging. 2023; 2(7):592-600. DOI: 10.1038/s43587-022-00244-6. View

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J . Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005; 280(20):19883-7. DOI: 10.1074/jbc.M413274200. View

Kronenberg H . Developmental regulation of the growth plate. Nature. 2003; 423(6937):332-6. DOI: 10.1038/nature01657. View

Takimoto A, Nishizaki Y, Hiraki Y, Shukunami C . Differential actions of VEGF-A isoforms on perichondrial angiogenesis during endochondral bone formation. Dev Biol. 2009; 332(2):196-211. DOI: 10.1016/j.ydbio.2009.05.552. View

Shukunami C, Takimoto A, Miura S, Nishizaki Y, Hiraki Y . Chondromodulin-I and tenomodulin are differentially expressed in the avascular mesenchyme during mouse and chick development. Cell Tissue Res. 2008; 332(1):111-22. DOI: 10.1007/s00441-007-0570-8. View

Apostolakos J, Durant T, Dwyer C, Russell R, Weinreb J, Alaee F . The enthesis: a review of the tendon-to-bone insertion. Muscles Ligaments Tendons J. 2014; 4(3):333-42. PMC: 4241425. View

Poole K, van Bezooijen R, Loveridge N, Hamersma H, Papapoulos S, Lowik C . Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005; 19(13):1842-4. DOI: 10.1096/fj.05-4221fje. View

10.

Baron R, Kneissel M . WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013; 19(2):179-92. DOI: 10.1038/nm.3074. View

11.

Dyment N, Breidenbach A, Schwartz A, Russell R, Aschbacher-Smith L, Liu H . Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis. Dev Biol. 2015; 405(1):96-107. PMC: 4529782. DOI: 10.1016/j.ydbio.2015.06.020. View

12.

Tits A, Ruffoni D . Joining soft tissues to bone: Insights from modeling and simulations. Bone Rep. 2021; 14:100742. PMC: 8190669. DOI: 10.1016/j.bonr.2020.100742. View

13.

Kawamoto T, Kawamoto K . Preparation of Thin Frozen Sections from Nonfixed and Undecalcified Hard Tissues Using Kawamoto's Film Method (2020). Methods Mol Biol. 2020; 2230:259-281. DOI: 10.1007/978-1-0716-1028-2_15. View

14.

Blitz E, Sharir A, Akiyama H, Zelzer E . Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors. Development. 2013; 140(13):2680-90. DOI: 10.1242/dev.093906. View

15.

Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J . Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res. 2009; 24(10):1651-61. DOI: 10.1359/jbmr.090411. View

16.

Ideo K, Tokunaga T, Shukunami C, Takimoto A, Yoshimoto Y, Yonemitsu R . Role of Scx+/Sox9+ cells as potential progenitor cells for postnatal supraspinatus enthesis formation and healing after injury in mice. PLoS One. 2020; 15(12):e0242286. PMC: 7707462. DOI: 10.1371/journal.pone.0242286. View

17.

Schwartz A, Long F, Thomopoulos S . Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment. Development. 2014; 142(1):196-206. PMC: 4299149. DOI: 10.1242/dev.112714. View

18.

Kawamoto T . Use of a new adhesive film for the preparation of multi-purpose fresh-frozen sections from hard tissues, whole-animals, insects and plants. Arch Histol Cytol. 2003; 66(2):123-43. DOI: 10.1679/aohc.66.123. View

19.

Hallett S, Ono W, Ono N . Growth Plate Chondrocytes: Skeletal Development, Growth and Beyond. Int J Mol Sci. 2019; 20(23). PMC: 6929081. DOI: 10.3390/ijms20236009. View

20.

Brunkow M, Gardner J, Van Ness J, Paeper B, Kovacevich B, Proll S . Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001; 68(3):577-89. PMC: 1274471. DOI: 10.1086/318811. View