Our study targets overweight middle-aged women who have OA in one knee. Half of the 432 study participants will receive the treatment (doxycycline) and half will receive a placebo (inactive pill). Treatment with doxycycline (or placebo) will last 30 months, and participants and researchers will not know who is receiving doxycycline and who is receiving placebo until the end of the study. We will look for narrowing of the joint space in the knee that was not affected by OA at the start of the study. Joint space narrowing is a sign of OA. We will also use questionnaires to evaluate participants' symptoms and functioning.