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.

Radiation therapy can result in bone injury with the development of fractures and often can lead to delayed and nonunion of bone. There is no prevention or treatment for irradiation-induced bone injury. We irradiated the distal half of the mouse left femur to study the mechanism of irradiation-induced bone injury and found that no mesenchymal stem cells (MSCs) were detected in irradiated distal femora or nonirradiated proximal femora. The MSCs in the circulation doubled at 1 week and increased fourfold after 4 wk of irradiation. The number of MSCs in the proximal femur quickly recovered, but no recovery was observed in the distal femur. The levels of free radicals were increased threefold at 1 wk and remained at this high level for 4 wk in distal femora, whereas the levels were increased at 1 wk and returned to the basal level at 4 wk in nonirradiated proximal femur. Free radicals diffuse ipsilaterally to the proximal femur through bone medullary canal. The blood vessels in the distal femora were destroyed in angiographic images, but not in the proximal femora. The osteoclasts and osteoblasts were decreased in the distal femora after irradiation, but no changes were observed in the proximal femora. The total bone volumes were not affected in proximal and distal femora. Our data indicate that irradiation produces free radicals that adversely affect the survival of MSCs in both distal and proximal femora. Irradiation injury to the vasculatures and the microenvironment affect the niches for stem cells during the recovery period.

Osteoporosis is a disease attributed to an imbalance in communication between osteoblasts and osteoclasts, possibly arising from a locally acidic microenvironment which hinders normal cell function. However, to date, little or no attention has been paid to these cells' milieu in respect of implant materials. Although it has been claimed for a few biomaterials that they stimulate bone formation, seldom has their surface behavior been invoked to explain behavior. With degradation, ion concentrations and pH at the material's surface must vary and thus may affect osteoblast response directly. On degradation of a recently developed biomaterial, Sr-containing CaSiO3, the interfacial pH was found to be appreciably higher than that of the bulk medium and the "standard" physiological value of 7.4. At these high values (pH > 8), both the proliferation and alkaline phosphatase (ALP) activity of osteoblasts was significantly enhanced, with a maximum response at 10% Sr substitution for Ca. This shows that the chemistry of the solid-liquid interface is a critical factor in bone regeneration, although this has generally been overlooked. Thus, the interfacial pH in particular is to be considered, rather than the bulk value, and this may be of importance in many related contexts in bone-tissue engineering.