Currently the clinical management of osteoporosis and age-related bone disease is limited to symptomatic treatment and is directed mainly at slowing the rate of bone loss by using agents that inhibit bone resorption. Yet, the number of patients with osteoporosis is growing exponentially and health care costs related to osteoporosis management are increasing accordingly. Thus, an ability to shift our paradigm of bone health from treatment to prevention to combat this rise in osteoporosis and its related complications would constitute a significant improvement in how osteoporosis is managed clinically. One such approach to preventing osteoporosis that holds promise is optimization of peak bone acquisition during pubertal growth. Growth hormone (GH) and its downstream effector insulin-like growth factor-1 (IGF-1) play critical roles in bone accrual during growth by regulating not only linear growth but also transversal bone growth, an important factor determining bone strength. The long-term goal is to determine the endocrine and autocrine/paracrine mechanisms by which the GH/IGF-1axis regulates skeletal integrity in normal physiology and age-related bone disease. The objective for this application is to elucidate the mechanisms by which activation of the GH receptor (GHR) in osteocytes controls bone accrual during pubertal growth. The overarching hypothesis is that osteocyte response to GH plays a central role in regulating the acquisition of bone mass, and does so via mechanisms independent from GH effects on linear growth. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following three specific aims: 1. Determine the mechanisms by which osteocyte-specific GHR regulates osteogenesis. 2. Determine the mechanisms by which osteocyte-specific GHR interacts with PTH and sclerostin to regulate peak bone mass. 3. Determine the mechanism(s) by which osteocyte- specific GHR modulates anabolic response to mechanical loading. An already-generated osteocyte- specific GH-receptor knockout (GHRKO) mouse will be used to achieve all aims. Importantly, initial characterization of this model has revealed blunted trabecular bone accrual and decreased cortical bone volume - all despite normal overall body size and bone lengths. Our new data showing that GH insensitivity in bone impairs PTH anabolic effects possibly involving sclerostin expression in bone, links our results closely to two skeletal regulators that are currently major targets of therapeutic interventions. The proposed approach is innovative because it focuses for the first time on osteocytes not only as mechanosensors and regulators of mineral homeostasis, but also as integrators of endocrine signals that control bone formation during growth. Further, we offer for the first time a direct approach to determine the extent to which local GHR action is necessary for osteocyte mechanoresponse. The proposed research is significant because it is expected to advance our understanding of how peak bone mass is achieved, ultimately leading to the development of interventions for the prevention of age-related bone loss.
The proposed research is relevant to public health because a mechanistic understanding of how peak bone mass is achieved during human development is ultimately expected to contribute to the development of new approaches to decrease the incidence of osteoporosis and its related complications later in life. Thus, the proposed research is relevant to the part of NIH's mission that pertains to seeking fundamental knowledge on human growth and development and to apply that knowledge to lessen the burdens of illness and disability.