Anti-LRP6 antibodies and antigen-binding fragments thereof, as well as pharmaceutical compositions comprising such antibodies and antigen-binding fragments are described. These anti-LRP6 antibodies can be used to enhance Wnt activity and/or antagonize Dkk1 activity. Also described are methods of therapy using such antibodies and antigen-binding regions to bind modulate Wnt/LRP6 signaling to promote tissue homeostasis, regeneration and repair in diseases such as, but not limited to, bone disorders, such as osteoporosis, rheumatoid arthritis, and osteolytic lesions caused by osteoarthritis and multiple myeloma, gastrointestinal disease and wound healing.