Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

Abstract

Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for osteoarthritis due to limited understanding of osteoarthritis pathogenesis. We show that TGF–β1 is activated in the subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) osteoarthritis mouse model. TGF–β1 concentrations also increased in human osteoarthritis subchondral bone. High concentrations of TGF–β1 induced formation of nestin+ mesenchymal stem cell (MSC) clusters leading to aberrant bone formation accompanied by increased angiogenesis. Transgenic expression of active TGF–β1 in osteoblastic cells induced osteoarthritis. Inhibition of TGF–β activity in subchondral bone attenuated degeneration of osteoarthritis articular cartilage. Notably, knockout of the TGF–β type II receptor (TβRII) in nestin+ MSCs reduced development of osteoarthritis in ACLT mice. Thus, high concentrations of active TGF–β1 in the subchondral bone initiated the pathological changes of osteoarthritis, inhibition of which could be a potential therapeutic approach.

IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

“…In OA, the degenerative changes in articular cartilage gradually percolate into the subchondral region as both are interdependent (30). ACL transection alters the joint biomechanics and subsequently leads to the development of OA (23). In our mouse model of human OA, the binary images of transaxial radiographs generated by m-CT of femoral subchondral bone showed destruction of trabecular microarchitecture within 8 d of ACL transection (Supplemental Fig.…”

“…The newly formed osteoclasts from these precursors along with resident osteoclasts promote subchondral bone resorption. OAassociated damage reaches its peak in 15 d and remains persistent thereafter (23). Evaluation of subchondral bone in OA mice showed significant damage to trabecular microarchitecture within 8 d of ACL transection and was observed until day 43.…”

TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts

“…Animal models revealing both positive [3][4][5] and negative [6][7][8] effects of TGF-β 1 on bone strength have been reported. Likewise, poor bone quality and delayed fracture healing in patients is associated with both the lack of TGF-β 1 and chronically elevated TGF-β 1 levels [9][10][11][12][13][14][15]. We have recently shown that continuous exposure to human recombinant TGF-β 1 (rhTGF-β 1 ) inhibits bone morphogenetic protein (rhBMP2 and rhBMP7)-dependent maturation of primary human osteoblasts (hOBs) in a histone deacetylase (HDAC)-dependent manner [16].…”

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

“…In osteoarthritis (OA), a degenerative joint disease, articular cartilage is degraded and osteophytes (ectopic bone) are formed, in part, by increased hedgehog signaling in articular chondrocytes, mimicking the endochondral ossification process (3,4). In addition, bone underlying the articular cartilage thickens, a response proposed to be a result of mechanical stress-induced TGF-β signaling in osteoblast precursors within the subchondral bone (5).…”