Cellular stressors are thought to cause dysfunction or death of osteoblast lineage cells (progenitors, bone-forming osteoblasts, and remodeling orchestrator osteocytes) and thereby cause bone loss in skeletal diseases. Autophagy is a cell stress-response pathway that recycles cellular components damaged by cellular stressors. There are three types of autophagy: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. These different types of autophagy differ in mechanism, target, and function. In addition to stress response, autophagy pathways also have cell-type-specific functions, such as controlling cell differentiation. We have previously shown that macroautophagy and CMA contribute to bone remodeling, albeit at different levels. Herein, we hypothesize that “Autophagy promotes the differentiation, survival, and function of osteoblast lineage cells”. In previous studies, we have shown that lack of macroautophagy resulted in decreased osteoblast numbers and bone formation. In Aim1, we will examine possible mechanisms by which lack of macroautophagy decreases osteoblast numbers and bone formation. Specifically, we will examine if lack of macroautophagy alters proliferation, apoptosis, or differentiation of osteoblast lineage cells. Our preliminary studies suggest that osteoblastic cells use CMA to protect from ER stress-induced cell death. In Aim 2, we will address if CMA plays a similar stress response role in vivo in a skeletal condition associated with ER stress, namely osteogenesis imperfecta (OI). The induction of macroautophagy has been shown to improve age- and aggregate-associated pathologies in other tissues. However, whether stimulation of autophagy can ameliorate skeletal pathologies is unknown. In OI, misfolded collagen forms aggregates and causes cellular stress. This is thought to decrease osteoblast function and contribute to the pathology of OI. In Aim3, we will increase macroautophagy capacity specifically in the osteoblast lineage cells and address if this clears collagen aggregates, relives ER stress, and improves OI skeletal pathology.