Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis.
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.
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.
Tristan W
TW
Fowler
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.|Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Claire
C
Acevedo
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.|UC Berkeley-UCSF Graduate Program in Bioengineering, University of California Berkeley, Berkeley, CA, USA.
Courtney M
CM
Mazur
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.
Faith
F
Hall-Glenn
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.
Aaron J
AJ
Fields
Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Hrishikesh A
HA
Bale
Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.|Department of Materials Science and Engineering, University of California Berkeley, Berkeley, CA, USA.
Robert O
RO
Ritchie
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.|UC Berkeley-UCSF Graduate Program in Bioengineering, University of California Berkeley, Berkeley, CA, USA.
Jeffrey C
JC
Lotz
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.
Thomas P
TP
Vail
Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.|UC Berkeley-UCSF Graduate Program in Bioengineering, University of California Berkeley, Berkeley, CA, USA.
Tamara
T
Alliston
D000818:Animals; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling / Q000187:drug effects*; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010011:Osteocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010020:Osteonecrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D011239:Prednisolone / Q000009:adverse effects*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D003692:Delayed-Action Preparations; D005938:Glucocorticoids; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D011239:Prednisolone; C000605510:ACP5 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase; C534130:CTSK protein, human; D056657:Cathepsin K; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14