In our aging population, osteoporosis is a major public health problem. Fragility fractures are associated with significant morbidity, loss of functional independence, and mortality. Bone mass is determined by the balance between bone formation by osteoblasts and bone resorption by osteocytes. A third cell type, the osteocyte, senses external signals to bone and relays this information to nearby osteoblasts and osteoclasts on bone surfaces. The Wein laboratory studies molecular mechanisms controlling osteocyte differentiation and function. To do this, we apply cutting edge technologies to define the circuitry crucial for osteocyte function.
Parathyroid hormone signaling
We recently found that PTH signaling in osteocytes works in large part by turning off salt inducible kinase function. Small molecule SIK inhibitors mimic PTH action, both in cultured osteocytes and in vivo. Now we are further investigating the PTH/SIK signaling axis in osteocytes, and pursuing small molecule SIK inhibitors as agents to treat osteoporosis, fracture healing, and osteoarthritis. In addition, we are exploring whether salt inducible kinases participate in PTH action in other target organs including kidney.
Mechanisms of mechanotransduction in osteocytes
It is known that osteocytes respond to mechanical cues, but exactly how this occurs is quite mysterious. We are using unbiased approaches to better understand the intracellular signaling pathways through which osteocytes sense and respond to mechanical forces.
Osteocytogenesis
Osteoblasts synthesize bone matrix and differentiate into osteocytes. The molecular pathways responsible for this fascinating differentiation event are unknown. We are using genomic approaches to try to better understand the process of osteocytogenesis, with the goal of identifying novel transcriptional regulators and signaling pathways that allow for this dramatic cellular transformation.
Other ideas?
We are always interested in new and exciting directions in skeletal biology, mechanotransduction, and parathyroid hormone action.
Just email Marc: mnwein@mgh.harvard.edu