Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels.

We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Wingless-type) antagonist sclerostin and found mutations disrupting this function to be associated with high bone mass in humans similar to patients lacking sclerostin. To further delineate the role of LRP4 in bone in vivo, we generated mice lacking Lrp4 in osteoblasts/osteocytes or osteocytes only. Lrp4 deficiency promoted progressive cancellous and cortical bone gain in both mutants, although more pronouncedly in mice deficient in osteoblast/osteocyte Lrp4, consistent with our observation in human bone that LRP4 is most strongly expressed by osteoblasts and early osteocytes. Bone gain was related primarily to increased bone formation. Interestingly, Lrp4 deficiency in bone dramatically elevated serum sclerostin levels whereas bone expression of Sost encoding for sclerostin was unaltered, indicating that osteoblastic Lrp4 retains sclerostin within bone. Moreover, we generated anti-LRP4 antibodies selectively blocking sclerostin facilitator function while leaving unperturbed LRP4-agrin interaction, which is essential for neuromuscular junction function. These antibodies increased bone formation and thus cancellous and cortical bone mass in skeletally mature rodents. Together, we demonstrate a pivotal role of LRP4 in bone homeostasis by retaining and facilitating sclerostin action locally and provide a novel avenue to bone anabolic therapy by antagonizing LRP4 sclerostin facilitator function.

Insidious destruction of the hip by Mycobacterium tuberculosis and why early diagnosis is critical.

Tuberculosis has re-emerged as an important problem in the United States. More than 10 million people presently are infected with Mycobacterium tuberculosis in the United States alone. The symptoms at first presentation of the disease have become more diverse. With extrapulmonary manifestations, such as musculoskeletal infections, as the sole presenting sign, it often can be difficult to determine the correct diagnosis early in the course of the disease. The presenting symptoms, physical signs, and radiographic findings of intra-articular tuberculosis can mimic those of other intra-articular diseases, such as rheumatoid arthritis, osteoarthritis, and avascular necrosis. In view of the nonspecific findings early in course of the disease, tubercular infection should be considered in the differential diagnosis when there is insidious articular destruction. Failure to consider tuberculosis can lead to devastating outcomes otherwise preventable with today's chemotherapies.