Epigenome, a record of the chemical changes to the DNA and histone proteins of an organism, is dynamically altered by environmental conditions and thus contributes to an adaptive mechanism for the given environmental stress. Among them, the cold environment is life-threatening to homeothermic animals. To combat, they induce thermogenic gene expression such as Ucp1 against cold stress. We recently revealed dual roles for the histone demethylase JMJD1A as a mediator of both acute and chronic thermogenic responses to cold stress, in two distinct thermogenic tissues, and through two distinct molecular mechanisms.

Romosozumab is a humanized anti-sclerostin monoclonal antibody that has just been approved for the treatment of osteoporosis in Japan. Romosozumab causes both transient stimulation of bone formation and continuous suppression of resorption, thereby increasing bone mineral density and decreasing fracture incidence. Because the effect of romosozumab is reversible, sequential therapy with anti-resorptives after romosozumab will be necessary. This overview summarizes the results of ARCH study demonstrating superior efficacy of romosozumab compared to alendronate and effect of sequential therapy with alendronate. Possible adverse effect of romosozumab on cardiovascular diseases will also be discussed.

Romosozumab is a bone-forming agent with a dual effect of increasing bone formation and decreasing bone resorption by inhibiting sclerostin. In the pivotal Fracture study in postmenopausal women with osteroposis(FRAME)and the extension trial, 12 months of romosozumab led to persistent fracture, especially new vertebral fracture, reduction benefit and ongoing BMD(bone mineral density)gains when follow 24 months of denosumab. The sequence therapy of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis.

Multiple myeloma(MM)develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. A variety of cytokines are overproduced in MM to stimulate RANKL-mediated osteoclastogenesis while suppressing osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. Soluble Wnt inhibitors elaborated from MM cells and/or their surrounding cells in bone lesions play an important role. Novel therapeutic neutralizing antibodies against DKK-1 or sclerotin are expected as bone anabolic agents;however, their effects on MM tumor progression through activation of the Wnt/β-catenin pathway remain to be carefully clarified.

Over the past 15 years, many studies have revealed that Wnt signaling has a strong impact on hematopoietic stem cell fate. After a controversy over the interpretation of some results, the current understanding is that an appropriate degree of canonical Wnt signaling induces hematopoietic stem cell self-renewal and that noncanonical Wnt signaling keeps the quiescence. It is also likely that the balance between canonical and noncanonical Wnt pathways regulates the stress response and aging of hematopoietic stem cells.

Bone erosions develop early in the course of rheumatoid arthritis(RA)and are predictive of a worse prognosis. They deteriorate gradually and cause joint damage, resulting in impaired functional capacity and disability. Lately, a considerable number of studies have increased our understanding of the pathogenic mechanisms participating in the development of bone erosions in RA. Osteoclasts are responsible cells and multiple factors have been identified to stimulate their differentiation and function. RANKL(receptor activator of NF-κB ligand)and other cytokines have been known for a long time to enhance osteoclastogenesis, but the role of other pathways has also been revealed recently. Besides to excessive ostaoclastogenesis, impair osteoblast differentiation and function also plays part in bone erosion formation in RA. Inflamed synovial membrane products increased levels of cytokines and antagonists of the canonical Wnt signaling pathway, which inhibit osteoblast differentiation and function. It seems that downregulation of this pathway leads to impaired osteoblast differentiation and activity and consequently, to reduced capacity of bone erosion to repair. Preclinical studies show that these findings could have implications in RA treatment, although more studies are required in this direction.

Wnt signaling is known to be involved in metabolic bone disorders. Serum levels of sclerostin, a bone-specific protein that inhibits Wnt signaling, have been investigated in a variety of metabolic bone disorders. Serum sclerostin levels are positively correlated with bone mineral density in patients with osteoporosis. Elderly women with high serum sclerostin levels, however, are at increased risk of bone fractures. Since serum sclerostin levels are low in primary hyperparathyroidism and high in hypoparathyroidism, parathyroid hormone could be classified as a factor that regulates sclerostin levels. Serum sclerostin levels are high in glucocorticoid-induced osteoporosis and diabetes mellitus, which feature reduced bone formation. Finally, serum sclerostin levels increase with decreasing renal function. These findings highlight the potential of serum sclerostin levels as a new index for bone assessments which are different in nature from bone mineral density and bone metabolic markers.

Identification of responsible genes for skeletal dysplasias evidences their critical roles in the skeletal development and maintenance. Mutations in the genes encoding the components of Wnt canonical pathway, which include WNT1, LRP5, LRP4, SOST and WTX, cause the disorders characterized by abnormal in bone mass. On the other hand, mutations in the genes for the components of Wnt non-canonical pathway such as WNT5A, ROR2, DVL1 and DVL3 are associated with dysmorphic skeletal disorders which manifest short limbs and facial anomalies. Thus, both canonical and non-canonical pathways of Wnt signaling play substantial roles in the human skeletons, and it is suggested that the former mainly controls bone mass while the latter regulates skeletal morphogenesis.

Osteocytes has many functions such as sensing mechanical stress to bone, regulating formation and activity of osteoclasts as well as modulation of bone metabolism and function of other organs through production of humoral factors such as sclerostin and FGF23. Sclerostin suppresses bone formation and stimulate bone resorption by inhibiting Wnt activity. FGF23 regulates phosphate metabolism mainly acting on kidney. In contrast, it is also reported that sclerostin works in kidney and FGF23 inhibits Wnt activity in osteoblasts. However, the physiological significance of these actions of sclerostin and FGF23 needs to be established by future investigations.

Wnt ligands activate β-catenin-dependent canonical and -independent non-canonical signaling pathways. Recent studies established importance of Wnt/β-catenin signaling in bone accrual. Antibodies against the Wnt inhibitor sclerostin and those against the Wnt inhibitor Dickkopf-1 have been shown to be effective for increasing bone mass. In addition to their effects on bone formation, roles of Wnt signals in bone resorption are gradually clarified. In this review, we would like to introduce recent advances in roles of Wnt signals in osteoclast formation and functions and regulation of sclerostin expression by osteoclasts.

Wnt plays important roles in regulation of differentiation of osteoblast and chondrocyte and their function. Wnt family members ingeniously utilize canonical Wnt signaling pathway through β-catenin and non-canonical Wnt signaling pathway independent of β-catenin, consequently regulating development, formation and homeostasis of bone and cartilage. Recent studies revealed that canonical Wnt signal activates transcriptional regulator, TAZ, in addition to transcription factors, LEF and TCF. Canonical Wnt signal crosstalks with BMP signal by stimulating complex formation of LEF1, TAZ and Runx2. Although molecular mechanism of non-canonical Wnt signal is getting clearer, the precise role of non-canonical Wnt signal in bone and cartilage seems still elusive.

Non-canonical Wnt signaling, including planar cell polarity and Ca2+ pathways, plays crucial roles in developmental processes, including morphogenesis and tissue-/organo-genesis, in animals. Ror2 receptor tyrosine kinase mediates non-canonical Wnt signaling by acting as a receptor for Wnt5a, which also inhibits canonical Wnt signaling. Dysregulation of Wnt5a-Ror2 signaling causes a wide range of developmental defects and cancer progression. Recently, Ror2-mediated non-canonical Wnt signaling has also been shown to induce formation of filopodia that facilitates transport of Wnt to neighboring cells, thereby activating canonical Wnt signaling there.

The Wnt signaling pathways are classified into the β-catenin dependent pathway, which regulates gene expression through β-catenin, and the β-catenin independent pathway, which does cytoskeletal rearrangement in a β-catenin independent manner. The former is also called as the canonical Wnt signaling pathway and extensively studied in development, tumorigenesis, and regenerative research. Recently, novel mechanistic insights into the canonical Wnt signaling pathway have been clarified through the analysis of structure of Wnt-receptor complex, regulation of Wnt signaling at the cell surface membrane, and intracellular protein complex of Wnt complexes.

The Wnt signaling pathway is known to play an important role in various biological processes including embryonic development and tissues homeostasis. Following the identification of the mutations in LRP5, encoding for the Wnt co-receptor low density lipoprotein receptor-related protein 5, associated with bone disorders in human, numerous studies have demonstrated the importance of Wnt signaling in bone cells. The Wnt signaling pathway is one of the key regulators of bone metabolism, hence the treatment using a monoclonal antibody against sclerostin, a bone-specific endogenous Wnt inhibitor, could improve bone mass and decrease fracture risk.

Apoptosis is a prototype of regulated cell death and plays a crucial role in the development of various organs and maintaining tissue homeostasis. Recent studies have revealed that new types of regulated cell death, including necroptosis, ferroptosis, and pyroptosis are molecularly identified. In this review, we discuss the molecular mechanisms and the functions of new types of regulated cell death.