Abstract
Subchondral bone deterioration and osteophyte formation attributable to excessive mineralization are prominent features in the progression of end-stage knee osteoarthritis (OA). The cellular events underlying subchondral bone integrity diminishment remained elusive. This study was undertaken to characterize behavior and intracellular signaling of subchondral mesenchymal stem cells (SMSCs) and bone-marrow MSCs (BMMSCs) in OA knees isolated from patients with end-stage knee OA underwent total knee arthroplasty. The SMSCs isolated from subchondral bone explants expressed remarkable surface antigens CD73, CD105, CD90, CD166, CD44, CD29, instead of MHC II, CD45, and CD31. The cell cultures exhibited high proliferation capacity concomitant with low population doubling time compared to those of BMMSCs. Incubation in differentiation media, the SMSCs showed high osteogenic and chondrogenic lineage commitment and low adipogenic differentiation potential. They also exhibited high expression of embryonic stem cell marker OCT3/4, osteogenic factors Wnt3a, β-catenin and microRNA-29a (miR-29a) in conjunction with low expression of joint-deleterious factors HDAC4, TGF-β1, IL-1β, TNFα, and MMP3. Loss of miR-29a function lowered HDAC4 level, mineralized matrix accumulation and osteogenic marker expression of SMSCs. miR-29a reduced HDAC4 translation through targeting the 3”-untranslated region of HDAC4, which concomitantly sustained Wnt3a and β-catenin signaling. Collectively, high osteogenic lineage commitment existed in the SMSCs in OA knee microenvironment. miR-29a modulation of HDAC4 and Wnt3a signaling contributed to the increases in osteogenesis. This study shines a light no the biological role of MSCs in subchondral compartment in the end-stage OA development and highlights a new source of MSCs for joint tissue repair.
