Aberrant subchondral bone remodelling is implicated in the development of osteoarthritis (OA), but how this process is induced and how increased bone turnover promotes articular cartilage degeneration is unclear. New findings implicate pre-osteoblast expansion and secretion of the chemokine CXCL12 mediated by the cellular energy sensor mTORC1.

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“Previous studies by our group and others have shown that balanced mTORC1 activity is critical for bone metabolism and development,” explains corresponding author Xiaochun Bai. “However, the role of mTORC1 in subchondral bone formation during the pathogenesis of OA and the underlying mechanisms have not been reported.”

The researchers used an inducible conditional-knockout approach to generate mice (referred to hereafter as ΔTSC1 mice) that lack TSC1 (a negative regulator of mTORC1) in pre-osteoblasts after doxycycline treatment, resulting in constitutive activation of mTORC1 in these cells.

ΔTSC1 mice had abnormal bone formation and bone sclerosis 6 weeks after doxycycline-treatment but their articular cartilage integrity was intact. However, in an anterior cruciate ligament transection (ACLT) model of post-traumatic OA, TSC1 deletion accelerated cartilage damage and OA development.

By contrast, disrupting mTORC1 activation in pre-osteoblasts of mice (through deletion of the mTORC1 component RAPTOR) reduced subchondral bone formation and articular cartilage degeneration in the ACLT model.

Interestingly, the pre-osteoclasts from ΔTSC1 mice had increased expression of CXCL12, and treatment with an anti-CXCL12 antibody attenuated ACLT-induced articular cartilage degeneration in ΔTSC1 mice.

disrupting mTORC1 activation… reduced subchondral bone formation and articular cartilage degeneration

“We have shown that pre-osteoblasts of subchondral bone might be another major source of abnormally increased CXCL12 expression in OA in addition to synovial tissue,” says Bai. “CXCL12 might target chondrocytes through the circulation to promote OA.”