Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis

Abstract

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causing degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Thus, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

“…A shorter time course or an inducible model would be needed to conclusively address this question. However, our previous studies have shown similar canalicular degeneration within 21 days of glucocorticoid treatment (Fowler et al, 2017) or a week of lactation (unpublished data)(Kaya et al, 2017; Qing et al, 2012; Qing and Bonewald, 2009; Wysolmerski, 2013), thereby indicating that changes in the canalicular network can occur rapidly in a manner that is independent of a maturation defect.…”

“…This study represents the most definitive evidence so far implicating osteocyte-mediated PLR in the control of bone quality. Previous studies by our group and others show that bone quality is impaired following glucocorticoid treatment or systemic ablation of MMP13, and that PLR is impaired in each case (Fowler et al, 2017; Lane et al, 2006; Tang et al, 2012). Here we find that osteocyte-specific deletion of TGFβ signaling caused defects in PLR and in cortical bone mineralization, flexural strength, ECM material properties, and fracture toughness without impacting cortical bone mass.…”

“…In this study, PLR mediated changes were observed at osteocyte canaliculi alone. Interestingly, emerging data from our lab and others (Fowler et al, 2017; Kaya et al, 2017; Tang et al, 2012) suggest that remodeling by osteocytes may be spatially defined, such that some circumstances favor remodeling at lacunae, whereas others will promote remodeling around canaliculi. Additional studies will be needed to determine the extent to which this is true.…”

“…The coordinated regulation of these PLR genes by TGFβ is consistent with the effects of other PLR-regulatory pathways. Most of these genes are induced by PLR agonists, such as sclerostin and PTH, but repressed by PLR antagonists such as glucocorticoids (Fowler et al, 2017; Kogawa et al, 2013; Qing et al, 2012). In each case, including in this study, these changes in gene expression correspond to alterations in the organization of the canalicular network.…”

“…In addition to alterations in the canalicular network, lactation and glucocorticoid treatment cause changes in lacunar size (Fowler et al, 2017; Qing et al, 2012). Furthermore, collagen organization is disrupted in MMP13-deficient mice and in mice treated with glucocorticoids.…”