Bone remodelling
Bone is generated and remodelled throughout life in cycles of tightly coupled osteoclastic and osteoblastic acivity.
The osteoclast is a giant multinucleated cell derived from the monocyte/macrophage population and is responsible for bone resorption. The key signals in monocyte-osteoclast differentiation and activation are macrophage-colony stimulating factor (M-CSF) and receptor activator of NFκβ (RANK) ligand respectively. RANK ligand (RANKL) on stromal cells and osteoblasts bind to RANK on osteoclast precursors causing fusion and, via activation of a number of intracellular signalling pathways such as c-src, leads to differentiation into mature osteoclasts. The RANKL system is controlled by osteoprotegerin (OPG), also produced by osteoblasts, that acts as a decoy receptor and reduces osteoclast activation. The up-regulation of RANKL and reduced OPG expression is, in part, reponsible for the increased osteoclast activation and bone degradation in inflammatory arthritis. Another recently-identified determinant of inflammatory bone loss is dickkopf-1 (DKK-1). DKK-1 is up-regulated in RA synovium in response to TNFα and inhibits wingless (wnt)-signalling. The downstream effects of this inhibition is twofold:
In health, resorption by osteoclasts is swiftly followed by the creation of new bone by osteoblasts.
Osteoblasts are mesenchymal stem cells. They are multipotent so their development into osteoblasts is promoted by a number of signals including bone morphogenic proteins, CBFA1 (core binding alpha factor 1), osterix and Wnt (see above); the activity of such pathways is modified by endogenous inhibitors such as sclerostin and DKK. Activation of Wnt signalling leads to the intracellular accumulation of β-catenin, leading to specific gene transcription and osteoblast formation.
Osteoblasts produce bone matrix. Initially they lay down unmineralised osteoid; within 10 days this scaffold becomes calcified to form bone. Osteoblasts are rich in alkaline phosphatase (ALP) and osteocalcin, which can be used as a marker of osteoblastic activity (see below).
The osteoclastic/blastic relationship underlying bone remodelling is further controlled by loading mechanics and both local signals (e.g. cytokines) and systemic factors (e.g. parathyroid hormone, vitamin D, thyroid and growth hormones).
Paget’s disease
Paget’s disease is the second most common disorder of bone metabolism after osteoporosis. The disease is rare under 40 years, but increases
with age and affects 5% of those over 55 years. It is characterised by excessive bone resorption, followed by rapid but disorganised new bone formation; the resultant bone is enlarged, deformed and weak. The most common sites are to be affected are the pelvis, lumbar spine and femur. Only 10-30% of patients experience any symptoms, so usually the diagnosis is made incidentally.