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.

Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, regulates bone mass in adulthood. We report that IGF-1 released from bone matrix stimulates osteoblastic differentiation of mesenchymal stem cell (MSCs) by activation of mTOR during bone remodeling. Mice knockout of IGF-1 receptor (Igf1r) in the preosteoblastic cells exhibited low bone mass and reduced mineral deposition rates. The MSCs recruited to the bone surface were unable to differentiate into osteoblasts. In age-related osteoporosis in humans, we found that marrow IGF-1 levels were 40% lower than controls. Similarly, the levels of IGF-1 in the bone matrix and marrow of aged rats were also decreased and directly correlated with the age-related decrease in bone mass. Notably, injection of IGF-1 with IGF binding protein 3 (IGFBP3), not IGF-1 alone, increased the level of IGF-1 in the bone matrix and stimulated new bone formation in old rats. Thus, IGF-1 released during bone resorption from bone matrix activates mTOR to induce osteoblast differentiation of MSCs in maintaining bone micro-architecture and mass.

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